Immune modulatory vaccines targeting tumor microenvironment antigens: recent advances in oncology and beyond

Mads Hald Andersen

doi:10.1038/s41392-026-02710-8

. 2026 Apr 10;11:130. doi: 10.1038/s41392-026-02710-8

Immune modulatory vaccines targeting tumor microenvironment antigens: recent advances in oncology and beyond

Mads Hald Andersen ^1,^✉

PMCID: PMC13068913 PMID: 41963297

Abstract

Immune modulatory vaccines (IMVs) are an emerging class of immunotherapies designed to expand anti-regulatory T cells (anti-Tregs) that selectively target immunosuppressive elements within the tumor microenvironment (TME). Unlike conventional cancer vaccines aimed at tumor-associated antigens on malignant cells, IMVs target tumor microenvironment antigens (TMAs), such as indoleamine 2,3-dioxygenase (IDO), PD-L1, arginase-1 (ARG1), and transforming growth factor-β (TGF-β), which are expressed by malignant, myeloid, regulatory, endothelial, and stromal populations. IMVs elicit both CD8⁺ and CD4⁺ T-cell responses: CD8⁺ T cells can mediate cytotoxic elimination of TMA-expressing suppressive cells, whereas CD4⁺ T cells can induce proinflammatory cytokine programs that reprogram myeloid and stromal compartments toward immune-permissive states. Through these combined cytolytic and modulatory mechanisms, IMVs remodel suppressive cellular networks, improve antigen presentation, enhance immune infiltration, and amplify endogenous tumor-specific immunity. Early-phase clinical studies targeting IDO and PD-L1 have shown robust immunogenicity, favorable tolerability, and encouraging activity across multiple solid tumors, particularly in combination with immune checkpoint blockade. A phase III study in first-line advanced melanoma recently demonstrated that a therapeutic vaccine, when combined with anti–PD-1 therapy, can improve progression-free survival in patients with metastatic disease. The strongest signal was observed in PD-1–naïve disease and in PD-L1–negative tumors. Next-generation IMVs directed against ARG1 and TGF-β aim to address immune exclusion and desmoplastic stroma and are being developed across peptide- and mRNA-based platforms with favorable safety profiles that support evaluation in earlier-stage settings. Beyond oncology, analogous microenvironment antigens are induced in chronic and acute infections, suggesting that IMV principles may generalize to settings where regulatory circuits constrain pathogen clearance.

Subject terms: Tumour immunology, Translational research, Drug development, Vaccines, Tumour immunology

Introduction

The idea of antigen-specific immune regulation can be traced to Niels Jerne’s immune network theory (1974), which proposed that the immune system regulates itself through mutual recognition between lymphocyte receptors.¹ Although elements of the original model were later revised, Jerne articulated a durable principle that immune homeostasis depends on tightly regulated interactions among immune cells and molecules that can recognize one another even in the absence of foreign antigens.² It is now established that the immune system functions as a dynamic network that preserves organismal integrity while eliminating elements deemed dangerous.³ Multiple regulatory mechanisms terminate immune responses after antigen clearance, return the system to baseline, and maintain tolerance to self-antigens.⁴ Regulatory T cells (Tregs) exemplify this principle. The landmark work by Sakaguchi identified Tregs as key mediators of peripheral tolerance, and subsequent studies established Foxp3 as a master regulator of Treg development.^5–8 These discoveries were recognized by the 2025 Nobel Prize. Mechanistically, Tregs suppress immune responses through contact-dependent inhibition (e.g., CTLA-4), secretion of immunoregulatory cytokines such as IL-10 and TGF-β, and consumption of growth factors such as IL-2.⁹ Immune regulation is not mediated by Tregs alone. Myeloid-derived suppressor cells (MDSCs),¹⁰ tumor-associated macrophages (TAMs),^11,12 tolerogenic dendritic cells (DCs),¹³ and regulatory B cells (Bregs)¹⁴ also contribute to immune balance and protection from uncontrolled inflammation and autoimmunity (Fig. 1). In cancer, these regulatory programs are co-opted to promote tumor survival and progression.^15–29 The tumor microenvironment (TME) is now recognized as a specialized ecosystem that sustains immunosuppression.³⁰ Tumors recruit and expand Tregs and Bregs, polarize macrophages toward suppressive phenotypes, accumulate MDSCs, and skew DCs toward tolerogenic states.^4,13 Cancer-associated fibroblasts (CAFs) contribute by secreting TGF-β and generating a dense extracellular matrix that restricts effector infiltration.³¹ Endothelial cells add suppression through abnormal vasculature and expression of checkpoint ligands.³² Together, these cell populations form a multilayered suppressive network that represents a major barrier to durable antitumor immunity.³³

Fig. 1 — Suppressive network of cells within the TME limiting TIL activity. TILs recognizing TAAs or TSAs enter the TME, where they can attack and lyse (*blue arrow*) malignant cells. The TME, however, is composed of a heterogeneous collection of cellular populations that suppress (*red inhibitory arrows*) these lymphocytes through multiple mechanisms. Representative examples depicted here include MDSCs inhibiting through the PD-1–PD-L1 axis, TAMs releasing ARG1 and engaging LAG-3 receptors expressed by TILs, tolerogenic DCs releasing IDO and binding CTLA-4 on TILs, Tregs and Bregs secreting immunosuppressive cytokines such as IL-10 and TGF-β, CAFs forming a dense extracellular matrix, TANs releasing ARG1, and malignant cells expressing PD-L1 to inhibit TILs through PD-1 interaction. These examples are illustrative, as individual regulatory cell populations employ several inhibitory pathways simultaneously, reflecting the functional plasticity and overlap of suppressive mechanisms between different cell types within the TME. Elimination or reprogramming of these TMA-expressing immunosuppressive cell populations can therefore produce broad immunological effects. TAMs and MDSCs, typically polarized toward an M2-like phenotype by IL-4, IL-10, and TGF-β, secrete mediators such as VEGF, ARG1, IDO, and IL-10, display limited antigen-presenting capacity, and recruit additional suppressive cells. MDSCs further enforce inhibition through reactive oxygen species and adenosine and promote Treg expansion. TANs are similarly recruited and polarized by TGF-β signaling into immunosuppressive states that dampen T-cell responses and foster regulatory networks; TANs commonly express TMAs such as PD-L1, ARG1, and IDO. CAFs contribute both structural and functional suppression by producing extracellular matrix components that restrict immune infiltration and by secreting TGF-β and recruiting myeloid suppressor cells. Tregs release IL-10 and TGF-β, express CTLA-4 and PD-L1, and limit IL-2 availability, collectively suppressing effector function. Finally, Bregs exert their suppressive activity predominantly through cytokine-mediated mechanisms, e.g., IL-10, IL-35, and TGF-β, and express immune checkpoint ligands such as PD-L1. A detailed understanding of the factors involved in immune evasion in malignant conditions is essential for the development of novel immune therapeutic treatment modalities in cancer. Together, these interacting suppressive elements form an interdependent network that constrains antitumor immunity but also provides multiple points for IMV-mediated intervention aimed at restoring immune activation and effector function within the TME. Figure created with BioRender.com

Over the past 15 years, immune regulation has been refined further by the identification of naturally occurring self-reactive T cells that can recognize and eliminate suppressive cells. Because these cells counteract immune suppression, eliminate regulatory cells, and enhance effector immunity through cytokine secretion, they were defined as anti-regulatory T cells (anti-Tregs).³⁴ Anti-Tregs are not defined by a dedicated lineage program analogous to FoxP3-driven Treg differentiation but rather by antigen specificity and an anti-suppressive effector program. Hence, anti-Tregs are named for their function, which is “anti” to that of classical regulatory cells whose defining activity is immunosuppression. Anti-Tregs may function as early responder helper T cells and illustrate that immunoregulatory networks are not exclusively suppressive in nature. Anti-Tregs recognize HLA-restricted peptides derived from regulatory proteins, collectively referred to as tumor microenvironment antigens (TMAs).³⁵ TMAs include metabolic enzymes such as indoleamine 2,3-dioxygenase (IDO)^36–39 and Arg1/Arg2,^40–43 immune checkpoints such as PD-L1 and PD-L2,^44–48 immunosuppressive cytokines such as TGF-β^49–52 and CCL22,⁵³ and transcription factors such as FoxP3.⁵⁴ The identification of anti-Tregs provides experimental support for Jerne’s concept of lymphocytes recognizing one another independently of pathogen-derived antigens and illustrates that autoreactive, effector T cells are not inherently pathogenic but can serve physiological regulatory roles.² Anti-Tregs exist at low frequencies in healthy individuals, can expand in inflammatory contexts, and, when activated, can dismantle suppressive networks through cytotoxicity and cytokine-driven reprogramming. Within immune-regulatory networks, anti-Tregs can counteract regulatory immune cells while being constrained by the suppressive mechanisms exerted by their targets (Fig. 2). Cells that drive suppression can also inhibit anti-Treg function through the same pathways used to restrain immunity more broadly. For example, arginase-1 (ARG1)-expressing myeloid cells deplete arginine and can impair the proliferation and effector function of ARG1-specific T cells. Similarly, PD-L1–specific T cells often express PD-1 and can be inhibited through engagement of the PD-1/PD-L1 axis upon encountering PD-L1–expressing tumor or stromal cells. Additional inhibitory cytokines and metabolic constraints may further limit anti-Treg activity within highly suppressive niches. Collectively, these observations support a model in which suppressive and counterregulatory effector cells operate within a tightly controlled immune network, reciprocally shaping one another to preserve homeostasis while permitting context-dependent activation.⁵⁵ In cancer, TMAs are expressed by tumor cells and by regulatory lymphocytes, myeloid populations, stromal fibroblasts, and endothelial cells. Anti-Tregs act upon these TMA-expressing populations and can counterbalance suppression across the tumor ecosystem.³⁵

Fig. 2 — Immune balance within the TME. TILs (*blue*) recognize HLA-presented TAAs and TSAs on the surface of tumor (*gray*) cells and subsequently exert effector functions toward tumor (*gray*) cells in the TME by releasing cytolytic mediators, e.g., perforin or granzymes that mediate cytolysis (*blue arrow*). Anti-Tregs (*green*) recognize HLA-restricted epitopes derived from the intracellular degradation of TMAs presented on the surface of both malignant (*gray*) and regulatory immune (*red*) cells. Upon recognition, they exert effector functions by releasing proinflammatory cytokines and granzymes that mediate cytolysis and reprogramming of their targets (*green arrows*). In this way, anti-Tregs directly (*green arrows*) target suppressive immune subsets and tumor cells while indirectly (*dashed blue arrow*) enhancing the function of TILs through cytokine-driven modulation of the microenvironment toward a more inflammatory and immune-permissive state. Conversely, both anti-Tregs and TILs are inhibited by the suppressive milieu of the tumor microenvironment (*red inhibitory arrows*), where regulatory and tumor cells employ, e.g., checkpoint engagement, inhibitory cytokines, and metabolic suppression to restrain their activity. This bidirectional interaction illustrates the dynamic balance between immune activation and suppression within the TME. The mutual regulation between these opposing cell populations, where anti-Tregs suppress regulatory cells and in turn are subject to suppression themselves, illustrates a finely tuned feedback loop that preserves immune homeostasis. Together, these cell types act as ‘balance players’ of the adaptive immune system, continuously modulating the threshold between immune activation and tolerance. Figure created with BioRender.com

Initial efforts to overcome tumor-induced immune suppression focused on pharmacologic blockade of inhibitory pathways at the level of effector lymphocytes.^56–60 PD-1 signaling renders T cells functionally nonreactive against cognate antigens,⁶¹ and PD-1 expression by tumor-infiltrating T cells is a major brake on spontaneous antitumor immunity in patients with cancer.⁶² Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 revolutionized oncology by demonstrating that suppressive circuits can be disrupted, resulting in durable tumor regression in subsets of patients.^11,63 However, checkpoint blockade primarily releases inhibitory signals on preexisting effector T cells and does not directly eliminate or reprogram immunosuppressive populations within the TME.⁶⁴ Tumors with low effector infiltration (“cold tumors”) or those dominated by myeloid and stromal suppression often remain resistant, underscoring the need for complementary strategies.^63,65–67

Immune modulatory vaccines (IMVs) are defined as vaccines designed to induce antigen-specific immune responses against TMAs, with the primary aim of eliminating or reprogramming immunosuppressive cell populations rather than directly targeting malignant cells. In contrast to conventional cancer vaccines or vaccine-plus-adjuvant formulations that primarily aim to enhance effector responses against tumor-associated antigens or tumor-specific neoantigens, IMVs exploit autoreactive T cells to dismantle suppressive immune networks. The discovery of anti-Tregs provided a direct rationale for this approach. IMVs activate anti-Tregs through vaccination with TMA-derived peptides or TMA-encoding mRNA, thereby expanding autoreactive CD8⁺ and CD4⁺ T cells directed against TMAs. Unlike conventional cancer vaccines that aim to activate cytotoxic T lymphocytes against malignant cells,⁶⁸ IMVs amplify T cells that target cellular sources of suppression and remodel the TME.^69–75 The principle of IMVs is depicted in Fig. 3. This population-level targeting may reduce vulnerability to single-pathway escape, but resistance can naturally still occur through impaired antigen presentation and compensatory activation of alternative suppressive circuits. IMVs therefore complement, rather than duplicate, ICIs: ICIs release inhibitory brakes on tumor-reactive effector cells, whereas IMVs generate or expand autoreactive T cells that attack the suppressive niches themselves. As detailed throughout this review, the IMV concept has progressed from basic discovery to clinical translation, with early trials demonstrating safety and immunogenicity and recent phase III melanoma studies indicating that therapeutic vaccination can improve progression-free survival in advanced disease.

Fig. 3 — Principles and mode of action of IMVs. IMVs are based on TMAs, which can be administered either as single antigens or in combination (1). Vaccination with TMAs induces the expansion of TMA-specific T cells, also known as anti-Tregs (2), which target immunosuppressive cells within the tumor microenvironment (TME), including TAMs, MDSCs, Tregs, and stromal cells such as CAFs (3). IMVs exert direct effects (4a), in which TMA-specific CD8⁺ T cells mediate cytotoxic killing of target cells, while CD4⁺ T cells secrete proinflammatory cytokines that reprogram these cells toward a proinflammatory, antitumor phenotype. IMVs also mediate indirect effects (4b), including broader immune activation within the TME, modulation of TAMs and CAFs, reduction of fibrosis, enhanced tumor cell killing by TILs, and increased activity of antigen-presenting cells (APCs), leading to improved T-cell priming and activation. The figure was created with BioRender.com

Anti-regulatory T cells: discovery and mechanistic framework

Intrinsic IDO- and PD-L1-specific immunity

The first evidence for anti-Tregs emerged from studies of IDO-specific T cells. IDO is a tryptophan-catabolizing enzyme strongly induced by interferon-γ and expressed by tumor cells, dendritic cells, macrophages, and endothelial cells.^76–79 Its enzymatic activity depletes tryptophan, generates immunosuppressive kynurenine metabolites, impairs effector T-cell proliferation, and promotes the differentiation of Tregs.^80–82 Preclinical studies with material from patients with melanoma, renal cell carcinoma, and breast cancer revealed that HLA-restricted peptides derived from IDO are naturally processed and presented and that T cells recognizing these epitopes can be detected ex vivo directly in cancer patients.^36,37,83 Importantly, circulating IDO-specific anti-Tregs are also present in healthy donors, although their frequency of detection is lower than that in patients with cancer. Both CD8⁺ and CD4⁺ IDO-specific T cells have been identified.^36,38,39,84

CD8⁺ IDO-specific T cells displayed cytotoxicity against IDO-expressing tumor cells as well as IDO⁺ dendritic cells and macrophages, thereby demonstrating that T cells could directly eliminate both malignant cells and immunosuppressive immune populations. CD4⁺ IDO-specific T cells secrete proinflammatory cytokines such as IFN-γ and TNF-α, contributing to local reprogramming of the TME. Together, these findings established IDO as the prototypical TMA and provided the first experimental demonstration that autoreactive T cells could dismantle suppression at its source.³⁶

Soon after, attention turned to PD-L1. PD-1 regulates immune responses by suppressing T-cell activity, inducing apoptosis of antigen-specific T cells, and preserving regulatory T-cell populations.⁸⁵ Its ligand, PD-L1, is a transmembrane protein that binds PD-1 to inhibit T-cell proliferation, cytokine secretion, and survival. PD-L1 is upregulated in many malignancies, enabling tumor immune evasion.⁸⁶ Consequently, the PD-1/PD-L1 axis has emerged as a central pathway of immune escape and a critical target in cancer therapy.⁸⁷

PD-L1 functions as a key immune checkpoint ligand that enforces T-cell exhaustion and tolerance when expressed by tumor cells, stromal cells, macrophages, and dendritic cells.⁸⁸ It is strongly induced by interferons, particularly IFN-γ, in the inflammatory tumor milieu. Remarkably, researchers discovered that PD-L1 is also a natural T-cell antigen.^45,89 Both CD8⁺ and CD4⁺ PD-L1-specific T cells were isolated from the blood of cancer patients,⁴⁴ and strikingly, such cells were also detectable in healthy donors, even directly ex vivo. This demonstrated that self-reactive T cells specific for suppressive molecules exist physiologically and form part of the normal immune repertoire.

Functionally, PD-L1-specific CD8⁺ T cells can lyse PD-L1⁺ tumor cells and immune cell targets, while PD-L1-specific CD4⁺ T cells produce IFN-γ and TNF-α, thereby generating an inflammatory environment that enhances antigen presentation and effector recruitment.^46,47 Moreover, costimulation with PD-L1–derived peptides in dendritic-cell–based vaccines significantly boosted both CD4⁺ and CD8⁺ T-cell responses in vitro.⁹⁰ These findings firmly established that PD-L1 is not only a ligand for therapeutic blockade with monoclonal antibodies but also a bona fide antigen visible to T cells and amenable to vaccination.

Expansion of anti-Tregs during inflammation

The existence of anti-Tregs can be viewed as a striking demonstration of antigen-dependent immune regulation. Unlike classical autoreactive T cells that recognize tissue-specific self-antigens and risk driving autoimmunity, anti-Tregs recognize epitopes derived from molecules expressed by immunoregulatory and stromal cells and exist in healthy individuals without any sign of autoimmune diseases.³⁴ Importantly, anti-Tregs are not pathological remnants of incomplete tolerance. Rather, they are naturally present at low frequencies in healthy individuals, suggesting a physiological role in maintaining immune balance by policing suppressive pathways and ensuring that regulation itself does not dominate. Under normal conditions, equilibrium between immune activation and suppression appears necessary for homeostasis. The role of self-reactive effector and suppressor cells within immune-regulatory networks is therefore multifaceted.

Professional antigen-presenting cells express immunoregulatory proteins such as PD-L1 and IDO, which are induced by interferons at sites of inflammation.^{78,88,91–98} Both are expressed in high amounts mainly in immune-suppressive cells, but they can be expressed by antigen-presenting cells, placental cells, nonhematopoietic cells, and even activated T cells in an inflammatory microenvironment, as both type I and II IFNs induce expression.^{78,88,91–98}

Anti-Tregs are induced by antigenic stimulation and undergo expansion under inflammatory conditions.⁹⁹ It was shown that interferons expand IDO-specific T cells by demonstrating that known IDO inducers, such as IFN-γ, lead to the expansion of IDO-specific T cells among human PBMCs without the need for additional stimulation.³⁶ In line with this, subcutaneous IFN-γ injections in C57 mice induced the expansion of PD-L1-specific T cells.¹⁰⁰ When these mice were sacrificed one week after IFN-γ treatment, their spleens exhibited a strong PD-L1-specific T-cell response directly ex vivo. Similarly, three days of treatment with the allergen DNFB led to an influx and expansion of PD-L1-specific T cells at the inflammation site.¹⁰⁰

Pathogen-driven inflammation provides further evidence for this principle. Cytomegalovirus (CMV) induces IDO expression in vivo, which is thought to confer an advantage to CMV-infected cells by enabling them to evade T-cell responses.¹⁰¹ Consistent with this, IDO-specific T-cell responses in the periphery have been associated with CMV-specific T-cell responses.³⁹ These findings highlight that anti-Tregs are not static remnants of tolerance but dynamically regulated components of the immune repertoire. Under homeostatic conditions, they persist at low frequencies, but during infection, tissue damage, or tumor development, when immunosuppressive molecules are induced, they expand proportionally, providing antigen-specific counterregulation.

Their existence, specificity, and function therefore challenge the longstanding immunological assumption that autoreactive T cells are either deleted during thymic development or inevitably harmful if they persist.¹⁰² It is clear that self-reactive T cells with high-affinity TCRs for self-peptide/HLA complexes undergo clonal deletion to maintain tolerance. However, Yu and colleagues demonstrated that clonal deletion prunes but does not completely eliminate self-reactive clones.¹⁰³ In fact, self-peptide-specific CD8⁺ T cells were present in similar frequencies to non-self-specific T cells in the blood of healthy humans. These self-reactive T cells were significantly more anergic than foreign-specific T cells, but they could be activated by sufficiently strong signals. Such cells may escape thymic selection not only to participate directly in pathogen defense but also to provide the immune system with an additional layer of regulatory capacity in the form of anti-Tregs, thereby contributing to immune homeostasis.

Anti-Tregs represent a distinct self-reactive T-cell population whose activation is tightly coupled to inflammatory contexts. Anti-Tregs are naturally present in healthy individuals, exhibit low baseline activity, and are functionally restrained by the same suppressive mechanisms exerted by their target cells. Their activation therefore occurs preferentially in highly immunosuppressive environments where TMAs such as IDO or PD-L1 are strongly induced. This context dependence, together with intrinsic anergy under homeostatic conditions, provides a physiological safeguard against systemic autoimmunity despite self-reactivity.

Anti-regulatory cells as counterparts to regulatory cells

Mechanistically, anti-Tregs differ fundamentally from classical tumor-specific CD8⁺ T cells. Whereas tumor-specific T cells primarily exert direct cytotoxicity against malignant cells and frequently develop terminal exhaustion phenotypes, anti-Tregs act by eliminating or reprogramming suppressive cell populations and by reshaping the local immune environment, thereby indirectly amplifying broader antitumor immunity. They exert immunomodulatory effects, acting as functional counterparts to traditional regulatory cells. Whereas conventional Tregs are defined by a suppressive program (classically FoxP3-associated) and exert restraint through mechanisms such as CTLA-4–mediated contact inhibition, IL-10/TGF-β production, and IL-2 consumption, anti-Tregs are defined by the opposite functional output. Anti-Tregs mediate antigen-specific effector activity directed against regulatory pathways and regulatory cells. Importantly, anti-Tregs should not be interpreted as a distinct differentiation state parallel to Tregs; rather, they represent conventional CD4⁺/CD8⁺ effector phenotypes whose defining feature is recognition of TMA-derived epitopes and execution of anti-suppressive functions that lift immunoregulatory constraints. When activated in experimental setups, IDO-specific T cells shifted cytokine profiles toward a Th1 phenotype, increased secretion of TNF-α and IL-6, reduced Treg frequencies, and decreased IL-10 production.³⁶ These changes not only counteracted local suppression but also reinforced proinflammatory conditions favorable to effector immunity. Similarly, PD-L1-specific T cells demonstrated the capacity to support broader immune responses. In vitro, PD-L1-specific T cells enhanced the expansion and effector function of CD8⁺ T cells directed against viral antigens. Costimulation with PD-L1-derived peptides further boosted the immunogenicity of dendritic-cell–based vaccines, amplifying both CD4⁺ and CD8⁺ responses.^45–47,90 IDO-specific T cells displayed similar helper-like properties by eliminating suppressive antigen-presenting cells, thereby creating conditions that facilitated stronger activity of other antigen-specific T cells.

Taken together, these findings illustrated for the first time that anti-Tregs extend their impact beyond the direct elimination of antigen-expressing suppressive cells. By reprogramming cytokine environments and lifting suppressive networks, they enhance immune responses against unrelated antigens and provide a form of “support” function. In this way, anti-Tregs not only dismantle suppression locally but also amplify systemic immunity, reinforcing their role as essential balance players within the immune system. Although the T-cell receptor repertoire of anti-Tregs is still not well described, emerging evidence suggests shared clonotypes across individuals and robust functional recall upon repeated inflammatory stimulation. Importantly, by directly killing suppressive antigen-presenting cells, anti-Tregs promote secondary priming and epitope spreading, a feature that distinguishes them from checkpoint blockade and small-molecule inhibitors.

Conceptual implications

Taken together, the discovery of anti-Tregs established a new paradigm in immunology.^2,104,105 The description of antigen-dependent immune regulation demonstrated that the immune system does not rely solely on antigen-independent suppressive mechanisms but also employs antigen-specific effector responses directed against regulatory pathways. Anti-Tregs are therefore not aberrant, autoreactive cells poised on the edge of pathology. Rather, they represent essential counter-regulators that are physiologically present in healthy individuals, inducible under inflammatory conditions, and capable of restoring immune balance by targeting suppressive niches.

Their therapeutic expansion through vaccination gave rise to the concept of IMVs, a strategy designed to harness this natural autoreactivity to dismantle immune suppression in cancer and potentially other diseases.¹⁰⁶ IMVs thus build directly on the physiological principle that autoreactive T cells can act as regulators of regulation itself, offering a novel way to recalibrate immune balance for therapeutic benefit.

Tumor microenvironment antigens (TMAs)

Traditional tumor antigens

The concept of TMAs represents a fundamental shift in how we define relevant targets for immunotherapy. For decades, cancer immunology has focused on TAAs or TSAs as the principal targets for T-cell–based immunotherapy.¹⁰⁷ TAAs are derived from proteins expressed on both tumor cells and normal tissues, typically at lower levels, and include differentiation antigens and overexpressed antigens.¹⁰⁸ TSAs, in contrast, are defined by their restricted expression in malignant tissue and include viral antigens as well as general and personal mutated neoantigens.¹⁰⁹ Each of these categories has shaped the design of therapeutic cancer vaccines, with TSA examples ranging from HPV-derived viral antigens such as E6 and E7¹¹⁰ to mutated driver genes such as BRAF,¹¹¹ CalR,^112,113 and KRAS¹¹⁴ to TAAs such as melanoma-associated differentiation antigens such as Melan-A/MART-1¹¹⁵ and gp100.¹¹⁶ Overexpressed proteins such as survivin,^117,118 Bcl-2,¹¹⁹ Bcl-X(L),¹²⁰ and other IAPs,¹²¹ hTERT,¹²² HER2/neu,¹²³ and WT1,¹²⁴ as well as cancer-testis antigens, have further extended the TAA repertoire. Some antigens once thought to be TSA, such as MAGE-A12, have later been detected in restricted normal tissues, raising safety concerns in therapeutic settings with cellular therapies.¹²⁵

The central attraction of TSAs lies in their specificity, since T cells targeting TSAs should, in principle, spare normal tissues and circumvent tolerance.¹⁰⁹ TSAs are therefore becoming central to therapeutic cancer vaccination. Personalized vaccines encode patient-specific neoepitopes using mRNA, synthetic long peptides, or dendritic cells. In melanoma, in addition to PD-1 blockade, it improves recurrence-free survival and broadens antitumor T-cell responses.¹²⁶ Public neoantigen vaccines instead target recurrent oncogenic drivers such as KRAS mutations. These vaccines induce robust CD4 and CD8 immunity, promote antigen spreading, and correlate with clearance of minimal residual disease (MRD) in pancreatic and colorectal cancers.¹¹⁴ Both approaches are now evaluated in adjuvant and MRD settings, where low tumor burden favors synergy with immune checkpoint inhibitors. Personalized vaccines address tumor heterogeneity but face logistical and manufacturing challenges.¹²⁷ Public neoantigen vaccines offer scalability but are limited to patients with specific driver mutations. Together, these strategies show how TSAs are moving from conceptual targets into clinically actionable interventions.

Although both TAAs and TSAs are important targets, they share a fundamental limitation in that they are confined to the malignant compartment and do not directly address the broader immunosuppressive networks of the TME. In contrast, TMAs are defined not by their tumor cell origin but by their expression in regulatory cells such as regulatory lymphocytes, stromal fibroblasts, endothelial cells, and myeloid-derived populations.³⁵ They may be induced by inflammatory cytokines and stress signals and are consistently present across diverse tumor types. Importantly, TMAs generate peptides that are naturally processed and displayed on HLA molecules, making them accessible on the surface of regulatory cells for recognition by both CD4⁺ and CD8⁺ T cells in humans. Because different TMAs are expressed by distinct cellular subsets in the TME, they collectively provide a map of suppressive pathways. Vaccines that target a single TMA may modulate one compartment, for example, MDSCs or CAFs, but by combining TMAs, IMVs can orchestrate a more profound remodeling of the entire microenvironment.

Metabolic enzymes

One of the most powerful suppressive strategies exploited by tumors is the manipulation of local metabolism.¹²⁸ Effector T cells depend on nutrients such as tryptophan and arginine for clonal expansion, cytokine production, and cytotoxicity.^77,129,130 By degrading these amino acids, tumors and their associated stromal cells create a state of nutrient starvation that enforces T-cell anergy and promotes regulatory phenotypes.

IDO is the archetypal enzyme mediating this effect. Its activity depletes tryptophan and generates kynurenine metabolites, both of which impair effector T-cell function and promote the differentiation of naïve CD4⁺ cells into FoxP3⁺ Tregs.^131,132 IDO expression correlates with poor prognosis in melanoma, ovarian cancer, colorectal carcinoma, and glioblastoma.^133,134 As described above, peptides derived from IDO were the first TMAs shown to be naturally presented on HLA molecules and recognized by CD8⁺ and CD4⁺ T cells in both healthy individuals and cancer patients.^38,84 IDO-specific T cells lyse IDO⁺ cancer cell lines of different origins, including melanoma cells and ex vivo–enriched leukemia cells, illustrating the universal character of TMAs across multiple human cancers. They also kill IDO-expressing myeloid cells, demonstrating that IDO functions not only as a suppressor but also as a target of counterregulation.³⁶ Furthermore, IDO-reactive CD4⁺ T cells respond to dendritic cells pulsed with IDO⁺ tumor lysates, underlining their cancer relevance.³⁹ Functionally, IDO-specific CD4⁺ T cells are proinflammatory, releasing interferon (IFN)γ and tumor necrosis factor (TNF)α.

IDO2 and tryptophan-2,3-dioxygenase (TDO) are additional enzymes contributing to tryptophan metabolism. IDO2 is expressed in subsets of immune and tumor cells.¹³⁵ TDO is aberrantly expressed in several tumor types, particularly gliomas and hepatocellular carcinoma.¹³⁶ Although T-cell reactivity has been detected against both IDO2³⁷ and TDO,¹³⁷ these responses remain less well studied than those against IDO1. TDO elicits both CD8⁺ and CD4⁺ T-cell responses in patients and healthy donors. In healthy individuals, TDO-reactive CD4⁺ T cells predominantly show a Th1 phenotype with IFN-γ and TNF-α secretion. In cancer patients, however, they display a more differentiated profile, with subsets producing IL-17 or IL-10 in addition to Th1 cytokines. In melanoma, IL-17-expressing TDO-specific responses have been associated with improved overall survival, while IL-10-expressing TDO-specific T-cell responses correlate with poorer outcomes.¹³⁷ Expanded TDO-specific CD8⁺ T cells can kill HLA-matched tumor cells of diverse origins, although the processed epitopes vary between tumor types. TDO thus represents a shared immunogenic target, but the phenotype of TDO-specific T cells differs between health and cancer, with implications for prognosis and therapy.

ARG1 and ARG2 constitute a parallel metabolic checkpoint. Expression of these enzymes in the TME results in arginine depletion.^{129,138–142} L-arginine deprivation downregulates expression of the T-cell receptor ζ chain and reduces T-cell cytokine production and proliferation. ARG1 is strongly expressed by MDSCs and TAMs,¹⁴³ while ARG2 is present in CAFs and certain tumor cells, particularly in desmoplastic tumors such as pancreatic ductal adenocarcinoma.^144,145 ARG2 expression correlates with fibrosis, immune exclusion, and poor survival.¹⁴⁶

Like tryptophan-depleting enzymes, both ARG1 and ARG2 are immunogenic. CD4⁺ and CD8⁺ T cells specific for ARG1 and ARG2 peptides have been identified in patients and are capable of secreting proinflammatory cytokines and directly killing ARG-expressing cells. ARG1-specific T cells can also recognize and react against dendritic cells and B cells expressing ARG1.^147–149 Martinenaite et al. mapped the ARG1 protein and identified a hotspot region (amino acids 161–210) frequently recognized by spontaneous T-cell responses in both cancer patients and healthy donors.¹⁴⁷ These preexisting ARG1-specific responses are part of the T-cell memory repertoire.⁴¹ Arg1-specific T cells have also been detected among melanoma TILs, and CD4⁺ T-cell clones recognizing the hotspot region could be isolated and expanded, demonstrating direct recognition of ARG-expressing cells. Complementary work by Martinenaite and Lecoq et al. showed that ARG1-specific CD4⁺ T cells target TAMs directly, reprogramming them toward a proinflammatory phenotype through IFN-γ and IL-2 secretion.¹⁵⁰ Importantly, ARG1-derived peptides were shown to be naturally processed and presented on MHC class II by TAMs, confirming ARG1 as a bona fide TMA and supporting the rationale for ARG1-based IMVs. Likewise, naturally occurring effector T cells specific to ARG2 have been described.⁴³ Cytotoxic ARG2-specific CD8⁺ T cells can specifically recognize ARG2-expressing activated Tregs and ARG2⁺ cancer cell lines,¹⁴⁵ highlighting their anti-regulatory function. Recently, ARG2-specific T cells were also found to recognize CTCL cells with regulatory phenotypes.¹⁵¹

Immune checkpoint molecules

The PD-1/PD-L1 axis has become a cornerstone of modern immunotherapy, with checkpoint-blocking antibodies transforming the treatment of melanoma, NSCLC, and multiple other cancers.¹⁵² As described previously, PD-L1 is not only a therapeutic target for checkpoint blockade but also qualifies as a TMA. PD-1 and its ligands PD-L1 and PD-L2 play central roles in the development of an immune-inhibitory TME that protects malignant cells from immune-mediated death.¹⁵³ Both PD-L1 and PD-L2 can be described as TMAs because they are recognized by specific T cells in patients with cancer,^{44,47,48,89,104} although most work has focused on PD-L1–specific recognition, with PD-L2 being less extensively studied. PD-L2 is structurally related to PD-L1 and functions as a ligand for PD-1. PD-L2-specific T cells have been identified,⁴⁸ and vaccination against PD-L2 may broaden checkpoint-directed immunity and provide a strategy to overcome resistance to PD-1/PD-L1 blockade.

PD-L1-derived peptides are naturally processed and presented by HLA molecules and are recognized by spontaneous CD4⁺ and CD8⁺ T-cell responses.^44,89 PD-L1-specific CD8⁺ T cells can lyse PD-L1⁺ melanoma cells and cutaneous T-cell lymphoma cells.^44,45 Consistent with these findings, Minami et al. demonstrated that PD-L1⁺ HLA-A24⁺ renal carcinoma cells can be killed by HLA-A24–restricted PD-L1–specific T cells.¹⁵⁴ PD-L1-specific CD4⁺ T cells secrete IFN-γ and TNF-α, thereby enhancing inflammation within the TME.

To explore the immune-modulatory functions of PD-L1–specific T cells, they were isolated and added to cultured peripheral blood mononuclear cells previously stimulated with known immune-dominant viral epitopes such as influenza and Epstein–Barr virus. This resulted in a marked expansion of virus-specific CD8⁺ T cells,⁴⁶ an effect that has been confirmed in other costimulation assays. For example, significantly higher numbers of virus-specific T cells were observed in cultures costimulated with a PD-L1 peptide epitope than in cultures costimulated with an irrelevant HIV epitope.⁴⁷ Likewise, costimulation with a PD-L1 epitope enhanced immune reactivity to a cellular-based cancer vaccine.⁹⁰ These findings suggest that PD-L1–specific T cells may contribute to the effector phase of immune responses not only by providing proinflammatory cytokines at the site of inflammation but also by directly eliminating PD-L1–expressing regulatory cells that inhibit PD-1⁺ effector T cells.

The primary physiological role of the PD-1 pathway is thought to be the regulation of effector T-cell responses to limit tissue damage. This pathway, therefore, becomes more important after T-cell activation rather than during the priming phase.^61,155 Accordingly, the presence of PD-L1–specific T cells during the activation phase may not support a proinflammatory response in the same way as during the effector phase. Indeed, stimulation with viral epitopes in the presence of already activated PD-L1–specific T cells has been shown to decrease the numbers of virus-specific T cells after two weeks of culture,⁴⁶ possibly due to PD-L1 expression on potent antigen-presenting cells. PD-L1 can also be expressed on activated T cells, and these PD-L1⁺ T cells mainly exert tolerogenic effects on antitumor immunity and display tumor-promoting properties. Targeting this immune population is therefore expected to be beneficial.⁸⁸ The effects of PD-L1–specific T cells thus appear to depend on the timing of their activation, the expression of PD-1 and PD-L1, and the state of the immune response. These factors should be carefully considered when targeting PD-L1 as a TMA.

Together, PD-L1 and PD-L2 illustrate another key principle of TMAs: checkpoint ligands are not merely inhibitory signals but antigenic targets in their own right, capable of eliciting spontaneous T-cell responses. Their widespread expression across tumor and stromal compartments makes them particularly attractive candidates for inclusion in combination IMV strategies.

Immunosuppressive cytokines and chemokines

Cytokines can be regarded as the language of the immune system, orchestrating cellular behavior across tissues. Within the TME, malignant and stromal cells often exploit specific cytokines to enforce tolerance and exclude effector lymphocytes. Among these, TGF-β and IL-10 stand out as archetypal immunosuppressive signals.

TGF-β is one of the most pleiotropic and powerful regulators of immunity and tissue homeostasis.¹⁵⁶ It is secreted in abundance by tumor cells, CAFs, and TAMs and is present at particularly high concentrations in desmoplastic tumors such as pancreatic ductal adenocarcinoma.^156,157 TGF-β enforces immunosuppression through multiple nonredundant pathways. It drives the differentiation of naïve CD4⁺ T cells into FoxP3⁺ Tregs, inhibits cytotoxic T-lymphocyte function, and restrains NK cell activity.^156,158,159 Beyond immune modulation, it promotes epithelial-to-mesenchymal transition (EMT) in tumor cells, enhances fibrosis, and contributes to immune exclusion by stiffening the extracellular matrix.¹⁵⁶ TGF-β expression diminishes the efficacy of immune checkpoint inhibitors in many patients because it promotes immune exclusion across several cancer types.¹⁶⁰

Despite its broad suppressive function, TGF-β can also be recognized by effector T cells. Peptides derived from TGF-β are naturally processed and presented on MHC molecules, and TGF-β-specific CD4⁺ T cells have been isolated from both healthy donors and patients with cancer.^49,50 These cells typically secrete IFN-γ and TNF-α upon stimulation, thereby counteracting the suppressive effects of cytokines. Holmström et al. demonstrated that both healthy donors and cancer patients harbor spontaneous CD4⁺ and CD8⁺ T-cell responses against multiple epitopes of TGF-β, including cytotoxic clones capable of killing TGF-β–expressing leukemia and myeloid cell lines in a TGF-β–dependent manner.^49,50 Intriguingly, the presence of TGF-β-specific T cells in pancreatic cancer patients has been correlated with improved survival, suggesting that they may contribute to spontaneous immune control in otherwise intractable tumors. Extending this observation, TCR sequencing of a pancreatic cancer patient revealed intratumoral CD8⁺ T cells specific for the immunodominant epitope TGF-β-15, which recognized autologous regulatory myeloid cells in a TGF-β–dependent fashion. The presence of such clones correlated with survival benefit after ICI/radiotherapy, further highlighting the clinical importance of TGF-β-specific immunity.⁵² Recently, an additional study demonstrated that multiple TGF-β-derived epitopes, particularly TGF-β-33, elicit strong CD4⁺ and CD8⁺ T-cell responses in both healthy donors and pancreatic cancer patients.¹⁶¹ Baseline immunity to TGF-β-33 and combined responses to TGF-β-15 and TGF-β-33 correlated with significantly improved overall and progression-free survival in PDAC patients treated with radiotherapy and checkpoint inhibitors. These findings provide a strong mechanistic and clinical rationale for developing multiepitope TGF-β vaccines to overcome immunosuppression and fibrosis in pancreatic cancer. A recent study reported that TGF-β-specific CD4⁺ T cells are detectable in both peripheral blood and bone marrow from a substantial proportion of patients with fibrotic malignancies collectively termed myeloproliferative neoplasms.¹⁶² Single-cell RNA sequencing of public datasets identified megakaryocyte progenitors that coexpress TGF-β and HLA class II molecules, and in vitro differentiated megakaryocytes from patients were able to activate and expand TGF-β-specific T cells. These findings suggest that TGF-β-specific immunity represents an adaptive response to chronic TGF-β elevation in the marrow niche and may be exploitable for immune-modulatory vaccination strategies aimed at modulating fibrosis and disease progression.

In murine models, vaccination with multiepitope TGF-β epitopes has been shown to attenuate fibrosis and promote effector cell infiltration, thereby converting “cold” tumors into immune-responsive ones.⁵¹ Recent preclinical work has revealed an unexpected and crucial requirement for IL-6 signaling in mediating the efficacy of TGF-β–directed IMVs.¹⁶³ In murine PDAC, Perez-Penco et al. demonstrated that vaccination with TGF-β–derived peptides increased intratumoral IL-6, largely through polarization of CAFs toward an IL-6–secreting phenotype. IL-6 proved indispensable, as blockade of the IL-6 receptor (IL-6R) completely abrogated the antitumor effect of the vaccine. Mechanistically, IL-6 signaling sustained the development of MHC-II–restricted CD4⁺ TGF-β–specific T cells, enhanced T-cell infiltration into tumors, and preserved proinflammatory macrophage subsets. Conversely, IL-6R blockade increased the infiltration of immunosuppressive macrophages, elevated ARG1 expression, and promoted CD4⁺ T-cell exhaustion. These findings establish IL-6 as a surprising but essential partner for TGF-β–specific immunity and underscore the importance of cytokine context in shaping IMV activity.

IL-10, another archetypal immunoregulatory cytokine, is produced predominantly by Tregs, TAMs, and MDSCs within the TME. IL-10 exerts its suppressive effects primarily through inhibition of antigen-presenting cell function, including suppression of dendritic-cell maturation, downregulation of costimulatory molecule expression, and attenuation of IL-12 secretion, thereby impairing Th1 polarization.^164,165 The net result is a shift toward tolerance and anergy, particularly in tumors with heavy myeloid infiltration. Like TGF-β, IL-10 is also processed and presented as an antigen (unpublished data). IL-10-specific CD4⁺ T cells have been detected in humans and secrete inflammatory cytokines upon recognition. Conceptually, targeting IL-10 through vaccination would not only blunt its direct suppressive effects but also reprogram myeloid and Treg populations, making it an attractive addition to IMV strategies.

Another chemokine-like factor that plays a central role in establishing a suppressive tumor milieu is CCL22.¹⁶⁶ Secreted by tumor cells and TAMs, CCL22 binds CCR4 on Tregs and serves as a dominant mediator of their recruitment into tumors, correlating with poor prognosis across multiple cancer types.^167,168 Martinenaite et al. identified a naturally processed HLA-A2–restricted epitope within the CCL22 signal peptide and demonstrated that CCL22-specific CD8⁺ T cells are present in both healthy donors and cancer patients.⁵³ These cells were cytotoxic against CCL22-expressing cancer and myeloid cells, and their activation reduced CCL22 levels in the microenvironment, thereby limiting Treg migration. Building on this, Lecoq et al. showed that CD4⁺ CCL22-specific T cells can also be detected in human PBMCs and ovarian cancer ascites.¹⁶⁹ Vaccination with CCL22-derived peptides induced both CD4⁺ and CD8⁺ responses in mice, reduced CCL22 expression in tumors, and delayed tumor growth. Functionally, stimulation of CCL22-specific T cells not only decreased CCL22 secretion but also enhanced IFN-γ production, reflecting a combined effect of depleting CCL22-producing cells and driving proinflammatory reprogramming.

These findings classify CCL22 as a bona fide TMA. By targeting CCL22 through vaccination, it may be possible to dismantle one of the key chemokine axes responsible for Treg recruitment, thereby converting the TME into a more immune-permissive state.

Transcription factors

Not all TMAs have direct immunosuppressive functions on their own; some are intracellular transcription factors that define regulatory cell identities and pathways. Although once considered inaccessible to immune recognition, these proteins are processed, loaded onto MHC molecules, and displayed at the cell surface, making them legitimate targets for anti-Treg responses.

FoxP3 is the master transcription factor of Tregs. In rodents, its expression defines the lineage and underpins the suppressive function of these cells.⁹ However, in humans, the biology is more complex because FoxP3 can also be transiently expressed by activated effector T cells.^170,171 Within tumors, Tregs are often highly enriched, forming one of the dominant immunosuppressive populations in the TME. They suppress effector T cells through cytokines such as IL-10 and TGF-β and directly interact with dendritic cells and cytotoxic T cells to restrain their activity.¹³⁴ FoxP3’s central role in immune regulation makes it an attractive TMA, since selective targeting of FoxP3-expressing cells could dismantle a key pillar of tumor-associated immune suppression.

FoxP3-derived peptides are naturally presented on HLA molecules, and FoxP3-specific T cells have been identified in cancer patients.^54,172 These anti-Treg responses are capable of producing IFN-γ and TNF-α and, in some cases, of directly killing FoxP3⁺ Tregs. The existence of FoxP3-specific immunity underscores the principle that transcription factors, despite their intracellular localization, are not immunologically silent. From a therapeutic perspective, FoxP3-directed IMVs could expand these natural responses, tipping the balance between regulation and effector function decisively in favor of tumor control. In support of this idea, Gilboa and colleagues showed in an animal cancer model that FoxP3-based vaccination induced FoxP3-specific T cells, eliminated FoxP3⁺ Tregs, and enhanced antitumor immunity.¹⁷³ Atherosclerosis studies likewise reported that FoxP3-specific T-cell responses substantially reduced the number of FoxP3⁺ Tregs, but this was accompanied by increased lesion formation.¹⁷⁴ Thus, while FoxP3-based vaccines are conceptually compelling, their application in humans remains uncertain, given both the risk of targeting activated effector T cells and adverse effects.

IκBα, a critical regulator of NF-κB signaling, represents another transcriptional target with immunological relevance.^175,176 NF-κB is a central pathway in immunity and oncogenesis, regulating the expression of inflammatory cytokines, survival factors, and adhesion molecules.¹⁷⁷ In many tumors, NF-κB activity is dysregulated, driving chronic inflammation, resistance to apoptosis, and the recruitment of suppressive cells. IκBα, a cytoplasmic inhibitor that restrains NF-κB, is frequently altered in cancer and in regulatory immune cells.^176,178 Aberrant IκBα expression contributes to immune evasion and tumor progression. Importantly, IκBα-derived epitopes are presented on MHC molecules and recognized by T cells.¹⁷⁹ The detection of IκBα-specific T cells indicates that this pathway can also be policed by anti-Tregs. Targeting IκBα through IMVs could simultaneously modulate tumor-intrinsic survival pathways and regulatory immune cells, thereby providing a double-edged mechanism of action.

Together, FoxP3 and IκBα exemplify the breadth of TMAs. They demonstrate that even nuclear transcription factors, once thought inaccessible to immune recognition, can elicit spontaneous T-cell responses. Their inclusion broadens the conceptual landscape of IMVs, showing that no class of regulatory molecules lies beyond the reach of antigen-specific immunity.

Lectins

Galectin-3 (Gal3) is an immunoregulatory lectin highly expressed in the TME by cancer cells, CAFs, TAMs, and Tregs.^180,181 Gal3 promotes tumor progression and metastasis by driving immune evasion, impairing T-cell receptor signaling, and inducing apoptosis of activated T cells.¹⁸² Recent work has demonstrated that spontaneous Gal3-specific T-cell responses exist in both healthy donors and cancer patients and that Gal3-derived peptide vaccination can expand CD8⁺ T cells capable of targeting Gal3-expressing suppressive cells.¹⁸³ In murine breast cancer models, Gal3 vaccination delayed tumor growth, reduced intratumoral Tregs and Gal3⁺ cells, and altered T-cell memory populations toward a more durable phenotype.¹⁸³ These findings identify Gal3 as a novel TMA.

Traditional tumor-associated antigens with stromal expression

The tumor microenvironment is not composed solely of immune and malignant cells. Stromal and angiogenic components are also critical, as they enable tumors to establish physical and metabolic niches that limit immune infiltration and effector function. Classical tumor-associated antigens were originally defined by their overexpression in malignant cells. In contrast, molecules such as survivin¹⁸⁴ and vascular endothelial growth factor, VEGF,^185,186 illustrate that proteins primarily associated with angiogenesis and tumor cell survival can also contribute to shaping the tumor microenvironment. These molecules are expressed predominantly by endothelial and stromal compartments rather than immune cells, where they support angiogenesis, stromal remodeling, and immune exclusion. Another example is the fibroblast activation protein FAP, which is overexpressed in cancer-associated fibroblasts and has been explored as a target for cancer immunotherapy, with previous studies indicating its capacity to modulate the stromal architecture of tumors.¹⁸⁷ While survivin, VEGF, and FAP are not classical immune-regulatory molecules and therefore represent borderline cases in the context of IMVs, their targeting nonetheless affects key stromal and vascular elements of the tumor microenvironment. For this reason, and in the interest of providing a comprehensive overview, these targets are briefly discussed here, while the primary focus of the review remains on classical TMAs and anti-Treg-mediated mechanisms.^184–187 Survivin is a member of the inhibitor of apoptosis (IAP) family.¹²¹ In normal adult tissues, survivin expression is minimal or absent, largely confined to embryogenesis and stem cell compartments. In contrast, it is expressed in virtually all proliferating tumor cells.^188,189 Importantly, survivin is also expressed in nonmalignant stromal components of the TME, particularly endothelial cells, which redefines it as a TMA. Immune recognition of survivin, therefore, has the potential not only to target tumor cells directly but also to disrupt the stromal support on which they depend. Survivin-derived peptides are naturally processed and presented, and survivin-specific CD8⁺ T cells are frequently detected in cancer patients.^{117,118,190–192} Clinical trials of survivin-based vaccines have confirmed safety and immunogenicity, although efficacy has been limited when the vaccines were used as monotherapy.^193–195

VEGF is the master regulator of angiogenesis.¹⁹⁶ Secreted by tumor cells, CAFs, and infiltrating myeloid populations, VEGF orchestrates the recruitment of endothelial progenitors, stimulates vessel sprouting, and sustains the chaotic vasculature typical of growing tumors. VEGF also exerts profound immune-modulatory effects, impairing dendritic-cell maturation, dampening antigen presentation, and fostering the recruitment of Tregs and MDSCs. VEGF-specific T cells have been identified in cancer patients, and several clinical trials have targeted VEGF or VEGFR to inhibit angiogenesis.¹⁹⁷

FAP is a membrane-bound serine protease selectively expressed on CAFs and, to a lesser extent, on tumor cells but is absent from most normal adult tissues.^198,199 Its expression is closely linked to fibrosis, extracellular matrix remodeling, and tumor progression, making it a hallmark of desmoplastic stroma. FAP-derived peptides are naturally processed and presented on MHC molecules, and FAP-specific CD8⁺ T cells have been identified in both preclinical models and patient samples.¹⁸⁷ These T cells can recognize and kill FAP-expressing CAFs and FAP⁺ tumor cells, thereby reducing fibrosis and disrupting stromal barriers that limit immune infiltration.^200,201 In murine models, FAP-targeted vaccination elicited strong T-cell responses that mediated dual antitumor effects: direct killing of tumor cells and depletion of CAFs. This resulted in decreased collagen deposition, reduced fibrosis, and improved infiltration of CD8⁺ effector T cells. Importantly, FAP vaccination was well tolerated, with no significant toxicity observed in normal tissues despite stromal targeting. By targeting both tumor cells and CAFs, FAP-directed IMVs provide a dual mode of action by eroding fibrotic barriers and igniting inflammation within the stromal niche.

Conceptual and translational prioritization of TMAs

Although a broad spectrum of TMAs has now been identified, their prioritization for clinical development has followed both historical and biological logic rather than a purely algorithmic selection process. IDO and PD-L1 were the first TMAs to enter clinical evaluation because they were among the earliest immunosuppressive molecules shown to be strongly induced within the tumor microenvironment, to play nonredundant roles in immune escape, and to be naturally recognized by autoreactive CD4⁺ and CD8⁺ T cells in patients as well as in healthy donors. Their discovery coincided with a paradigm shift in tumor immunology, including the recognition of regulatory T cells and checkpoint pathways as central drivers of immune suppression.

Initial clinical development, therefore, focused on melanoma and non-small cell lung cancer, tumor types characterized by inflammatory microenvironments in which IDO and PD-L1 are frequently upregulated and where immune modulation had already demonstrated therapeutic relevance. As the IMV concept matured, target selection expanded deliberately beyond inflammatory TMAs toward antigens that dominate in poorly inflamed or immune-excluded tumors. In this context, ARG1 and TGF-β emerged as prioritized targets because they are highly expressed by suppressive myeloid cells and cancer-associated fibroblasts in tumors characterized by metabolic suppression, fibrosis, and limited effector T-cell infiltration.

Thus, TMA selection for IMV development is guided by the dominant suppressive mechanisms operating within a given tumor microenvironment, with IDO and PD-L1 prioritized in inflamed settings and ARG1 or TGF-β prioritized in stromal-rich or immune-excluded tumors. This adaptive and context-dependent prioritization strategy underpins both current combination approaches and the expansion of IMVs into tumor types that have historically remained resistant to immunotherapy. An overview of important TMAs is presented in Table 1.

Table 1.

List of tumor microenvironment antigens (TMAs)

Category	TMA	Primary expression sites	Main functions in immune suppression	Evidence of immunogenicity
Metabolic enzymes	IDO1	Tumor cells, DCs, macrophages, and endothelial cells	Depletes tryptophan, generates kynurenine, and induces Tregs	CD4⁺/CD8⁺ T-cell responses in cancer patients and healthy donors
	IDO2	Immune and tumor cells	Tryptophan catabolism	T-cell reactivity detected
	TDO	Gliomas, HCC	Tryptophan catabolism; immune suppression	CD4⁺/CD8⁺ responses (Th1, IL-17, IL-10)
	ARG1	MDSCs, TAMs	Arginine depletion, suppresses T-cell function	CD4⁺/CD8⁺ T cells specific for ARG1 peptides; cytokine secretion
	ARG2	CAFs, Tregs, tumor cells	Arginine depletion, fibrosis	Cytotoxic CD8⁺ responses
Checkpoint ligands	PD-L1	Tumor cells, DCs, macrophages, T cells	Inhibits T-cell activation, promotes exhaustion	Spontaneous CD4⁺/CD8⁺ responses in patients and donors
	PD-L2	APCs, tumor cells	PD-1 ligand, immune suppression	PD-L2-specific T cells detected
Cytokines/chemokines	TGF-β	Tumor cells, CAFs, TAMs	Induces Tregs, fibrosis, EMT, and immune exclusion	CD4⁺/CD8⁺ T-cell responses; correlated with survival
	IL-10	Tregs, TAMs, MDSCs	Suppresses DC function, Th1 polarization	IL-10-specific T cells detected
	CCL22	Tumor cells, TAMs	Recruits CCR4⁺ Tregs	HLA-A2–restricted cytotoxic CD8⁺ T cells
Transcription factors	FoxP3	Tregs	Master regulator of Tregs	FoxP3-specific CD4⁺/CD8⁺ responses
	IκBα	Tumor and regulatory immune cells	NF-κB pathway regulation	IκBα-specific T cells identified
Lectins	Galectin-3 (Gal3)	Cancer cells, CAFs, TAMs, Tregs	Impairs TCR signaling, promotes apoptosis of T cells	Gal3-specific T cells found in donors and patients
Traditional TAAs	Survivin	Tumor cells, endothelial cells	Inhibits apoptosis	Frequent spontaneous T-cell reactivity
	VEGF / VEGFR	Tumor cells, CAFs, endothelium	Angiogenesis, tolerance, Treg/MDSC recruitment	VEGF-specific T cells detected
	FAP	CAFs	Fibrosis, immune exclusion	FAP-specific CD8⁺ T cells detected

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Mechanisms of action of anti-Tregs

Anti-Tregs are unique because they recognize TMA-derived peptides expressed by both cancer cells and immune cells within the TME (Fig. 2). Mechanistically, anti-Tregs should be viewed as TMA-specific effector T cells that dismantle suppression (by killing or reprogramming suppressive cells), rather than as a regulatory lineage variant; this functional definition distinguishes them from conventional Tregs, whose defining role is to impose suppression.

CD8⁺ anti-Tregs as cytotoxic effectors

CD8⁺ anti-Tregs are defined by their cytotoxic capacity. They recognize TMA-derived peptides presented on MHC class I molecules, for example, IDO on tumor cells,³⁶ ARG1 on myeloid cells,²⁰² or PD-L1 on dendritic cells,⁴⁴ and upon activation, they release perforin and granzyme. The immediate consequence of this process is the elimination of the antigen-expressing cell, while the broader outcome is the removal of all suppressive functions mediated by that cell. As an illustration, the killing of an IDO-expressing dendritic cell not only abolishes IDO enzymatic activity but also eliminates IL-10 secretion, tolerogenic conditioning of T cells, and kynurenine-driven induction of Tregs.¹⁰⁵ In vitro studies have confirmed this principle by showing that IDO-specific CD8⁺ T cells efficiently eliminate IDO-expressing immune cells, which relieves the suppression of neighboring effector T cells.³⁶ In a similar manner, ARG1-specific CD8⁺ T cells were able to eliminate patient-derived regulatory myeloid cells, and this effect restored the proliferation of autologous cytotoxic T cells in coculture assays.¹⁵⁰ These findings demonstrate that the elimination of a suppressive myeloid cell has ecosystem-wide consequences, since this process removes ARG activity but also abolishes additional suppressive pathways, including adenosine production, TGF-β secretion, generation of reactive oxygen species, and impaired antigen presentation. It is also important to recognize that CD8⁺ anti-Tregs are not only cytotoxic but also act as potent cytokine producers. They secrete IFN-γ and TNF-α, which may directly impact target cells or diffuse within the TME and influence neighboring cells that may not express the cognate antigen. Through this mechanism, they enhance antigen presentation, promote recruitment of effector lymphocytes, and drive inflammatory reprogramming of macrophages and stromal populations.

CD4⁺ anti-Tregs as cytokine producers and reprogrammers

CD4⁺ anti-Tregs complement the cytotoxic activity of CD8⁺ cells through potent cytokine-driven reprogramming. When they recognize TMAs presented on MHC class II molecules, for example, peptides from PD-L1,²⁰³ TGF-β,⁵⁰ or ARG1,¹⁵⁰ they typically secrete high levels of proinflammatory cytokines such as IFN-γ and TNF-α. These mediators profoundly alter the functional state of suppressive populations. TAMs decrease IL-10 and ARG1 expression while increasing IL-12, nitric oxide, and costimulatory molecules. Dendritic cells improve their antigen-presenting capacity, and endothelial cells upregulate adhesion molecules such as ICAM-1 and VCAM-1, thereby facilitating lymphocyte recruitment. In coculture experiments, PD-L1-specific CD4⁺ T cells induced autologous macrophages to produce IL-12, significantly enhancing their ability to activate effector T cells (manuscript in preparation). TGF-β-specific CD4⁺ T cells secrete IFN-γ, which reduces fibrosis and improves immune infiltration in pancreatic tumor models,⁷⁰ demonstrating that cytokine-driven effects can extend beyond the antigen-bearing cells themselves. Functionally, ARG1-specific CD4⁺ T cells have been shown to reprogram patient-derived TAMs into proinflammatory states through secretion of IFN-γ and IL-2, providing direct evidence that CD4⁺ anti-Tregs serve as powerful re-educators of myeloid cells.¹⁵⁰

Although cytokine production is their dominant function, CD4⁺ anti-Tregs can also exert direct cytotoxicity. TGF-β-specific CD4⁺ T cells have been shown to kill TGF-β–expressing leukemia and myeloid cell lines in an antigen-dependent manner.⁵⁰ In addition, ARG1-specific CD4⁺ T cells were demonstrated to directly kill myeloid target cells.¹⁵⁰ These observations highlight that the division of labor between CD4⁺ and CD8⁺ anti-Tregs is not absolute, since both subsets are capable of cytotoxicity as well as cytokine-driven modulation.

Dual mechanisms and bystander effects

As described above, the functional impact of anti-Tregs involves both direct cytotoxicity and indirect modulation of the TME (Fig. 4). Direct killing eliminates antigen-expressing cells together with their associated suppressive functions. Indirect effects are mediated by proinflammatory cytokines that extend to neighboring cells regardless of whether they present the cognate TMA. For example, IFN-γ broadly enhances MHC expression, thereby improving antigen presentation throughout the TME, while TNF-α increases vascular permeability and facilitates effector cell infiltration. Many tumor cells downregulate surface HLA expression as a mechanism of immune evasion, yet HLA expression can often be restored in a proinflammatory milieu. In this way, immunological therapies that target nontransformed cells with consistent HLA expression can activate proinflammatory cascades in the TME, which may in turn reinduce HLA expression on tumor cells.

The dual mechanism of action of anti-Tregs has been confirmed in experimental systems. Elimination of IDO⁺ dendritic cells removed not only enzymatic IDO activity but also IL-10 production and defective antigen presentation.³⁶ Targeting ARG1⁺ MDSCs by ARG1-specific T cells abolished the full suppressive repertoire of these cells, both directly and indirectly.¹⁵⁰ In murine models, vaccination with TGF-β epitopes reduced stromal collagen and promoted infiltration of effector T cells. These effects resulted from the direct elimination of myeloid cells and CAFs as well as indirect bystander mechanisms mediated by cytokine release from TGF-β–specific CD4⁺ T cells, which reprogrammed fibroblasts and other stromal elements.⁷⁰

Modulation of specific suppressive cell populations

The elimination or reprogramming of TMA-expressing cells induces widespread effects throughout the TME, as each suppressive cell type simultaneously engages multiple nonredundant inhibitory pathways. The network of immune-suppressive cells within the TME, limiting effector lymphocyte activity, is depicted in Fig. 1.

(i)
Myeloid cells. TAMs, MDSCs, and tolerogenic DCs are abundant in solid tumors. The former is frequently polarized into an M2-like phenotype under the influence of IL-4, IL-10, and TGF-β.^204,205 In this state, TAMs secrete mediators such as VEGF, ARG1, IDO, and IL-10 while exhibiting poor antigen-presenting capacity and recruiting additional suppressive populations. MDSCs and DCs likewise enforce suppression through ARG1, IDO, reactive oxygen species, and adenosine, and they actively promote the expansion of Tregs. As already described in this review, these regulatory myeloid subsets express multiple TMAs and are therefore prime targets for anti-Tregs, which can eliminate or reprogram them and thereby dismantle a wide array of suppressive mechanisms within the TME.
(ii)
TANs are recruited into the TME, where they acquire extended lifespans and exert a profound influence on cancer progression.²⁰⁶ While neutrophils can adopt both antitumor and protumor phenotypes, the latter dominates in many solid tumors, where TANs promote proliferation, angiogenesis, invasion, and metastasis. Through pathways such as TGF-β signaling, TANs are polarized toward an immunosuppressive state that fosters tumor growth, dampens T-cell responses, and supports regulatory populations. Notably, TANs express several TMAs, including PD-L1, ARG1, and IDO, which directly contribute to the suppression of effector T cells and reinforcement of regulatory networks. TANs have emerged as key suppressive players within the TME and attractive targets for therapeutic reprogramming.
(iii)
CAFs are central architects of the TME, producing extracellular matrix proteins that stiffen the stroma and form a physical barrier to immune infiltration. Beyond their structural role, CAFs actively suppress immunity by secreting TGF-β, recruiting myeloid suppressor cells, and providing metabolic support to tumor cells.³¹ Importantly, CAFs express TMAs such as ARG2, TGF-β, and FAP, making them direct targets for anti-Tregs.^43,70,201 Vaccination with TMA antigens has been demonstrated to reduce fibrosis and promote effector lymphocyte infiltration in murine models. Through both their immunosuppressive activity and their role in enforcing stromal rigidity, CAFs represent a major barrier to effective antitumor immunity but also a promising target for IMVs designed to dismantle the suppressive tumor stroma
(iv)
Lymphocytes, both Tregs and Bregs, are a dominant suppressive force in tumors. Tregs secrete IL-10 and TGF-β, express checkpoint molecules such as CTLA-4 and PD-L1, and consume IL-2.²⁰⁷ Their accumulation correlates with poor prognosis across cancers. Both ARG2-, IDO-, and FoxP3-specific anti-Tregs can recognize and dismantle this compartment.^36,145,173 Eliminating Tregs in this way relieves checkpoint-mediated inhibition, reduces suppressive cytokines, and restores IL-2 availability to effector cells. In cancer, Bregs exert their suppressive activity predominantly through cytokine-mediated mechanisms.^208–210 The best characterized mediators are IL-10 and IL-35, with additional contributions from TGF-β and immune checkpoint ligands such as PD-L1. Bregs suppress CD8 T-cell effector function, reduce IFN-γ and TNF-α production, and promote the differentiation and expansion of FoxP3-positive Tregs. Thus, Bregs have been shown to mediate reduced effector differentiation as well as chemokine receptor expression in both CD8 T cells and NK cells.¹⁴

The targeting of these many suppressive cell types by anti-Tregs in the TME is depicted in Fig. 5. Consequently, the design of IMVs should be adapted to the cellular and antigenic landscape of each tumor context.

Remodeling of the TME

Although TMAs constitute the antigenic interface for anti-Treg recognition, the consequences of this interaction extend well beyond neutralization of the individual molecule. Because TMA-expressing cells typically deploy multiple immunosuppressive pathways simultaneously, their elimination or functional reprogramming leads to the dismantling of entire suppressive networks. The cytotoxic removal of myeloid-derived suppressor cells, for example, abolishes not only ARG or IDO activity but also the associated production of IL-10, TGF-β, reactive oxygen species, and adenosine. Similarly, the reprogramming of TAMs reduces IL-10 and ARG expression while enhancing the secretion of IL-12 and nitric oxide. Targeting CAFs alleviates stromal rigidity and diminishes chemokine-mediated immune exclusion, whereas depletion of Tregs eliminates both checkpoint ligand dominance and suppressive cytokine production. In this way, anti-Treg activity directed against discrete TMAs results in broad ecosystem-level remodeling of the TME. Consequently, when an anti-Treg eliminates or reprograms a TMA-expressing cell, the effect extends to the removal or alteration of the entire repertoire of suppressive activity contributed by that cell. This distinction represents the central mechanistic difference between IMVs and monoclonal antibodies or small molecules that inhibit only a single pathway. Anti-Tregs reshape the tumor ecosystem by directly targeting the cellular sources of suppression and, at the same time, enriching the microenvironment with proinflammatory mediators released upon their activation.

As outlined above, experimental evidence from in vitro systems, patient-derived cells, and murine vaccination models corroborates these mechanisms across diverse TMAs. This mechanistic breadth provides the foundation for IMVs, since the expansion of anti-Tregs enables the simultaneous dismantling of multiple suppressive networks and the restoration of conditions that support durable effector immunity. Taken together, IMVs exert dual mechanisms of action that operate in coordinated pairs across multiple immunological levels. This paired design integrates complementary processes that collectively reshape the tumor immune landscape and can be summarized as follows:

Dual activation: IMVs activate both CD4⁺ and CD8⁺ T cells
Dual targets: malignant cells and immunosuppressive cells.
Dual functions: direct cytolysis and cytokine-driven reprogramming.
Dual effects: direct effects on targeted cells and indirect remodeling of neighboring cells through inflammatory reconditioning of the microenvironment toward immune activation.

Potential resistance and escape mechanisms

IMVs target TMA-expressing suppressive cell populations, and escape is therefore expected to arise less from classical tumor cell antigen loss and more from microenvironmental adaptation. Resistance can still occur if key target populations reduce TMA expression or limit antigen presentation, for example, through HLA downregulation on myeloid, stromal, or endothelial targets. Suppression may also be maintained through compensatory programs, including expansion of alternative suppressive cell subsets or upregulation of redundant inhibitory pathways and non–PD-1 checkpoints. Finally, vaccine-expanded clones can become functionally constrained within hostile niches, including metabolic deprivation and sustained inhibitory signaling, and in heavily pretreated settings may adopt dysfunctional or exhaustion-like states. These considerations support multi-TMA targeting and rational combinations that prevent compensatory suppression while preserving effector function.

Preclinical development of immune-modulatory vaccines

In the preceding sections, the biology of anti-Tregs, their dual mechanisms of cytotoxicity and cytokine-driven modulation, and the identity of TMAs together with their expression across regulatory and stromal populations have been described. Building on this foundation, the focus now turns to the development of IMVs, which apply these principles in translational settings. The rationale of IMVs is to expand natural anti-Treg responses against TMAs expressed by tumor, myeloid, stromal, and regulatory cells, thereby dismantling the suppressive networks that drive tumor growth and immune exclusion. The following section reviews the preclinical evidence showing that IMVs against TMAs can reprogram the TME and alter tumor growth dynamics, providing the basis for subsequent clinical translation.

IDO and PD-L1 vaccination in preclinical models

The first preclinical demonstration of IMVs was provided by Dey and colleagues in the BALB/c CT26 colorectal carcinoma model.²¹¹ Vaccination with IDO-derived peptides significantly delayed tumor growth as monotherapy, establishing that expansion of endogenous IDO-specific T cells was sufficient to alter tumor progression. The antitumor effect was strictly dependent on IDO expression, since no benefit was observed in Ido1⁻/⁻ hosts, confirming that immune recognition targeted IDO expressed in host cells rather than in tumor cells. Immunofluorescence and flow cytometry localized IDO expression to a subset of infiltrating CD45⁺CD11b⁺CD11c⁺ immune cells with B-cell characteristics, demonstrating that the vaccine primarily acted on suppressive myeloid populations rather than malignant cells. Mechanistically, both CD4⁺ and CD8⁺ T cells contributed. Adoptive transfer experiments showed that class I–restricted peptides elicited CD8⁺ cytotoxic T cells that mediated direct antitumor effects, while class II–restricted peptides induced CD4⁺ helper T cells whose activity was fully IDO dependent. CD8⁺ T cells also displayed a component of IDO-independent activity, consistent with antigen spread, underscoring that IMVs can broaden the antitumor response beyond the targeted epitope. Finally, combining the IDO peptide vaccine with anti–PD-1 blockade produced markedly superior tumor control compared with either treatment alone. In some animals, this combination resulted in complete and durable tumor regression, highlighting that targeting IDO-expressing immune cells and simultaneously relieving PD-1–mediated inhibition acts through complementary pathways to overcome tumor-induced immunosuppression.²¹¹

Subsequent studies in the B16 melanoma model further demonstrated the potential of IDO vaccination.²¹² In this system, vaccination with IDO-derived peptides delayed tumor growth and improved survival compared with untreated controls. The therapeutic effect was mediated by the expansion of IDO-specific CD8⁺ T cells that lysed IDO-expressing dendritic cells ex vivo. Tumors from vaccinated animals showed reduced infiltration of MDSCs and increased infiltration of tumor-specific, effector CD8⁺ T cells, providing direct evidence that the removal of a single suppressive cell type can produce reverberating effects across the microenvironment.²¹²

Chapellier and colleagues first demonstrated that PD-L1 peptide vaccination likewise significantly delayed tumor growth in both MC38 and CT26 murine models.²¹³ Vaccination induced robust PD-L1–specific CD4⁺ and CD8⁺ T-cell responses, detectable in spleens, lymph nodes, and tumor-infiltrating lymphocytes. These T cells secreted IFN-γ and TNF-α upon restimulation and were capable of eliminating PD-L1⁺ target cells in vitro. Importantly, vaccinated animals showed evidence that PD-L1–specific T cells migrated into tumors, where they reduced local immunosuppression and promoted a proinflammatory shift. When PD-L1 vaccination was combined with IDO-targeted vaccination, Chapellier et al. reported that the dual approach enhanced tumor control compared with either vaccine alone. First, this expands both IDO- and PD-L1–specific T-cell responses and promotes their accumulation in tumors.²¹⁴ The combined vaccination remodeled the TME by reducing immunosuppressive gene signatures and increasing markers of cytotoxic T-cell activity. The findings further demonstrated that IDO and PD-L1 IMVs dismantle distinct suppressive pathways

Arginase vaccination and myeloid reprogramming

The first evidence for the therapeutic potential of ARG-targeted IMVs came from the work of Aaboe Jørgensen and colleagues, who demonstrated that vaccination with ARG1-derived peptides elicited strong T-cell responses in murine tumor models without toxicity.⁴² In both melanoma and colorectal carcinoma models, vaccination delayed tumor growth, increased CD4⁺ and CD8⁺ infiltration, and reduced intratumoral ARG1 expression. The functional consequences were evident in the myeloid compartment, where the balance of TAM polarization shifted toward a proinflammatory state, and myeloid cells isolated from vaccinated mice exhibited reduced suppressive activity. Depletion and transfer experiments confirmed that both CD4⁺ and CD8⁺ T cells contributed to tumor control, with CD4⁺ T cells providing dominant IFN-γ secretion. Importantly, the addition of anti–PD-1 therapy further enhanced tumor control, producing synergistic effects on survival and, in some animals, long-term protection upon rechallenge. These findings were extended by Lecoq and Martinenaite et al., who dissected the underlying mechanism in more detail.¹⁵⁰ They showed that ARG1-specific CD4⁺ T cells directly recognized naturally processed ARG1 epitopes presented by TAMs and responded with IFN-γ and IL-2 secretion. This cytokine production reprogrammed TAMs into proinflammatory antigen-presenting cells, characterized by increased expression of HLA-DR and costimulatory molecules and reduced levels of suppressive markers such as CD206 and TREM2. In this reprogrammed state, TAMs not only lose their suppressive capacity but also gain the ability to prime and activate effector T cells more effectively. Notably, human ARG1-specific CD4⁺ T-cell clones reprogrammed patient-derived myeloid cells in vitro, confirming that ARG1 peptides are naturally processed and presented in the human setting.¹⁵⁰

ARG2 vaccination extended these principles to the stromal compartment. In pancreatic ductal adenocarcinoma (PDAC), ARG2 is expressed in CAFs, where it contributes to fibrosis and the formation of a dense extracellular matrix that excludes lymphocyte infiltration.^43,145 Vaccination with ARG2-derived peptides in murine PDAC models reduced CAF numbers, decreased collagen deposition, and loosened the extracellular matrix. As a result, tumors that were previously immune-excluded became infiltrated by CD8⁺ effector T cells, effectively converting them from immunologically “cold” to “hot.” These findings provide compelling evidence that stromal fibroblasts, once thought to be immunologically invisible, can be targeted and remodeled through antigen-specific vaccination. In addition, ARG2-specific T cells can directly target activated Tregs.

TGF-β vaccination

The immunogenicity of TGF-β was also established in preclinical studies. In murine pancreatic and colorectal tumors, vaccination with TGF-β–derived peptides elicited CD4⁺ T cells that secreted IFN-γ and TNF-α, reduced fibrosis, loosened the extracellular matrix, and increased infiltration of both CD8⁺ T cells and NK cells.⁵¹ These changes delayed tumor growth and demonstrated that even a pleiotropic cytokine such as TGF-β could be targeted immunologically. More detailed mechanistic work showed that TGF-β–specific T cells exert their effects both through direct cytotoxicity against TGF-β–expressing myeloid and stromal cells and through cytokine-driven reprogramming of bystander cells.⁷⁰ In pancreatic tumor models, these T cells reduced the abundance of myCAFs and reprogrammed macrophages from an M2-like suppressive phenotype to an M1-like inflammatory state. Importantly, the efficacy of TGF-β vaccination was found to depend critically on IL-6.¹⁶³ Blockade of the IL-6 receptor abrogated the therapeutic benefit despite preserved CD8⁺ responses, underscoring that the success of TGF-β–specific immunity is shaped by the broader cytokine milieu.

Additional preclinical IMV models

The CCL22 chemokine is secreted by tumor cells and TAMs and recruits CCR4⁺ Tregs into the tumor, correlating with poor prognosis across multiple cancers. Lecoq et al. showed that CD4⁺ CCL22-specific T cells could be detected in PBMCs and ovarian cancer ascites and that vaccination with CCL22-derived peptides induced both CD4⁺ and CD8⁺ responses in mice, reduced intratumoral CCL22, and delayed tumor growth.¹⁶⁹ Functionally, stimulation of these T cells enhanced IFN-γ production, indicating that CCL22-directed vaccination not only depletes chemokine sources but also reprograms the microenvironment toward inflammation.

Beyond these classical immunoregulatory molecules, preclinical studies extended IMVs into stromal and angiogenic pathways. Vaccination with survivin-derived peptides elicited CD8⁺ T cells in murine tumor models and was safe and immunogenic in early clinical testing.²¹⁵ The DNA vaccine encoding survivin induced robust CD8⁺ T-cell responses after oral delivery via attenuated Salmonella. This dual targeting suppressed angiogenesis and triggered tumor cell apoptosis, leading to the eradication or suppression of lung metastases in murine models without impairing wound healing or fertility. VEGF and VEGFR vaccines provided clear evidence of stromal and angiogenic targeting. In glioblastoma and colon carcinoma models, DNA vaccination against VEGF reduced tumor volume and microvessel density and significantly prolonged survival, demonstrating direct antiangiogenic activity and immune control of tumor growth.²¹⁶ In pancreatic cancer models, VEGFR vaccination increased the CD8⁺ to Treg ratio in tumors, consistent with remodeling of the TME toward an immune-permissive state.²¹⁷ These findings confirm that angiogenic factors, long considered primarily stromal support molecules, can also function as TMAs and be effectively harnessed for immune attack.

Principles emerging from preclinical studies

Across a wide range of experimental models, IMVs consistently demonstrated the ability to reshape the TME and delay tumor progression as monotherapies. Their activity has been shown to be antigen-specific, reproducible, and mechanistically diverse, combining direct cytotoxic elimination of suppressive cells with cytokine-mediated reprogramming of surrounding populations.

A central lesson from these studies is that the targeting of even a single TMA can dismantle several suppressive pathways simultaneously. Elimination of MDSCs removes not only ARG1 activity but also the associated production of IL-10, TGF-β, adenosine, and reactive oxygen species. Reprogramming of TAMs substitutes suppressive mediators such as IL-10 and ARG1 with proinflammatory factors, including IL-12 and nitric oxide. Targeting CAFs reduces stromal stiffness and fibrosis, thereby enabling effector infiltration, while interference with chemokines such as CCL22 disrupts the recruitment of Tregs. Stromal and angiogenic TMAs such as survivin and VEGF provide additional points of intervention, as their elimination deprives tumors of critical vascular and structural support.

IMVs make it possible to dismantle immune suppression, inflame otherwise resistant tumors, and convert immune-excluded microenvironments into immune-permissive ones. The ability of IMVs to remove barriers that limit effector cell function also makes them highly attractive partners for T-cell–enhancing therapies such as anti–PD-1 blockade. Indeed, several of the preclinical studies reviewed here demonstrated that IMVs not only exert antitumor effects as monotherapy but also markedly enhance the efficacy of anti–PD-1 therapy, highlighting their promise as combination partners in immunotherapy.

Clinical development of immune-modulatory vaccines

The clinical development of IMVs has progressed in a remarkably rapid and stepwise fashion. Initial first-in-human studies were designed as small safety-oriented monotherapy trials, but they quickly demonstrated that vaccination could expand antigen-specific anti-Tregs in patients without provoking systemic autoimmunity. These early findings mirrored preclinical observations, confirming that anti-Tregs exist physiologically in humans, can be selectively and safely expanded through vaccination, and are capable of reprogramming the TME. Building on this foundation, clinical development advanced with unusual speed from early safety and feasibility studies to larger trials, including ongoing phase III evaluation. A defining feature of this trajectory has been the consistent demonstration that IMVs not only function as safe and immunogenic monotherapies but also act synergistically with standard checkpoint blockade. In combination with PD-1 inhibition, IMVs have repeatedly produced enhanced clinical activity, providing durable benefit across multiple tumor types and establishing their potential as a new therapeutic class within modern oncology.^218,219

First-in-human studies: IDO vaccination

The translational significance of anti-Tregs was first demonstrated in the initial clinical proof-of-concept study of an immune-modulatory vaccine. In this phase I trial, patients with advanced non-small cell lung cancer were vaccinated with an HLA-A2–restricted peptide derived from indoleamine 2,3-dioxygenase.²¹⁸ These heavily pretreated patients received repeated subcutaneous administrations of the IDO peptide formulated in Montanide ISA-51. Vaccination was safe and consistently immunogenic, inducing measurable expansion of IDO-specific CD4⁺ and CD8⁺ T cells in peripheral blood in all evaluable patients. Importantly, a reduction in circulating regulatory T cells was observed after six vaccinations, providing direct mechanistic evidence that the vaccine dismantled immune suppression at the cellular level.

Clinical outcomes were highly encouraging. Median overall survival reached 25.9–26 months in vaccinated patients, compared with approximately 7.7–8 months in contemporaneous HLA-A2–negative patients enrolled in the same protocol who did not receive vaccination. Nearly half of the vaccinated cohort achieved clinical benefit, defined as stable disease lasting more than 8.5 months or objective tumor response, and one patient experienced continuous tumor regression for more than one year. Clinical responses correlated with higher baseline frequencies of IDO-specific T cells, and sustained ELISPOT reactivity was observed in long-term responders, indicating durable functional immunity. Together, these correlative findings suggest baseline IDO-specific T-cell reactivity as a candidate predictive biomarker that warrants prospective validation.

Remarkably, two patients continued monthly vaccination for five to seven years, receiving more than 50 doses each, and remained progression-free for up to seven years without evidence of immune-related toxicity or autoimmunity.²¹⁹ In these individuals, IDO-specific T-cell responses persisted in peripheral blood for years after treatment initiation, confirming the long-term stability and tolerability of vaccine-induced anti-regulatory T cells.

Together, this first-in-human study provides definitive clinical proof that IMVs can safely expand autoreactive anti-regulatory T cells, reduce suppressive immune cell populations, and translate their preclinical mechanism of action into durable clinical benefit. It further demonstrated that self-reactive T cells can exist physiologically without causing toxicity and can be therapeutically harnessed to counteract immune suppression in cancer.^218,219

PD-L1 and PD-L2 vaccination

Encouraged by the results of IDO vaccination, PD-L1 was selected as the next TMA to enter clinical testing. In a first-in-human phase I trial, ten patients with multiple myeloma in remission following high-dose chemotherapy and autologous stem cell support received repeated subcutaneous vaccinations with a long PD-L1 peptide in Montanide adjuvant.²²⁰ The regimen, consisting of up to 15 doses over one year, was well tolerated, with no autoimmune events and only grade 1–2 injection-site reactions. Importantly, all vaccinated patients developed PD-L1–specific T-cell responses, detectable both in peripheral blood and in skin-infiltrating lymphocytes after delayed-type hypersensitivity testing. Functional analyses demonstrated the secretion of IFN-γ and TNF-α, confirming the proinflammatory profile of vaccine-induced T cells. Clinically, three patients experienced improvements in the depth of response during the vaccination period, and incidental regressions of basal cell carcinomas were observed in two individuals, consistent with the systemic activity of PD-L1–specific T cells. Although the small sample size and posttransplant setting limited efficacy evaluation, the study provided clear proof of safety and immunogenicity and established a foundation for subsequent phase II trials exploring the long PD-L1 peptide both as monotherapy and in combination with other vaccines or checkpoint blockade. A subsequent first-in-human trial in follicular lymphoma evaluated the combination of the PD-L1 long peptide with a peptide derived from the PD-L2 protein.²²¹ Eight patients in remission or partial remission after standard therapy received repeated vaccinations over one year. The regimen was well tolerated, with only mild flu-like symptoms and grade 1–2 injection-site reactions, and no cumulative toxicity was observed. Vaccine-induced T-cell responses were detected against both PD-L1 and PD-L2 in all patients, with PD-L1 responses generally stronger and more frequent. Importantly, early clinical signals were observed, with one patient converting from partial to complete remission, two patients experiencing pseudoprogression followed by durable regression, and another showing reductions in minimal residual disease. These findings confirm that checkpoint ligands can be safely targeted by vaccination and are capable of inducing both immune activation and early clinical benefit in lymphoma patients.

Combination of IDO/PD-L1 vaccines with PD-1 blockade

The encouraging signals from the initial phase I studies provided the rationale for a phase II program with the IDO-derived peptide entitled ‘IO102’ and the long PD-L1-derived peptide entitled ‘IO103’. Together, they represent the most clinically advanced IMV program to date. In the Phase II MM1636 trial, IO102/IO103 combined with nivolumab as first-line therapy for metastatic melanoma demonstrated a response rate of approximately 80%, with nearly half of the patients achieving complete responses.²²² With extended follow-up, the median progression-free survival reached 25.5 months, and the median overall survival was not reached after almost four years of observation.²²³ These outcomes compared very favorably to matched historical controls treated with anti–PD-1 alone, where the median progression-free survival was 8.3 months, and the median overall survival was 23.2 months. Clinical benefit extended across adverse prognostic subgroups, including patients with high LDH, stage M1c disease, or PD-L1–negative tumors, underscoring the robustness of the effect. Immune monitoring confirmed the induction of vaccine-specific CD4⁺ and CD8⁺ T cells that trafficked into tumors, where they not only targeted malignant cells but also reprogrammed suppressive myeloid populations, consistent with the mechanistic principle of TME repolarization.

Beyond the strong clinical efficacy, correlative analyses from the Phase II MM1636 study provided important potential biomarkers for clinical response. Serum proteomic profiling using the Olink platform identified a vaccine-specific immune signature characterized by early induction of CCL3, CCL4, and TNFα, which was associated with long progression-free survival.²²⁴ This early serum signature should be regarded as a candidate predictive/pharmacodynamic biomarker and should be tested prospectively to guide patient stratification and to inform rational sequencing and combination strategies. In particular, these cytokine shifts were not observed in a matched cohort receiving anti–PD-1 monotherapy, indicating that the vaccine contributed to distinct systemic immune modulation. Functional assays confirmed that vaccine-expanded IDO- and PD-L1–specific T cells induced secretion of these cytokines upon interaction with myeloid cells in vitro.

Building on these findings, a recent phase III trial evaluated IO102/IO103 in combination with pembrolizumab in more than 400 patients with advanced melanoma.²²⁵ The combination achieved a median progression-free survival of 19.4 months compared with 11.0 months for pembrolizumab alone, representing among the longest median progression-free survival reported in a phase III melanoma trial. The prespecified threshold for statistical significance was narrowly missed in the overall population (hazard ratio 0.77, nominal p = 0.06). Because these phase III data are currently available in abstract form and because the ITT population likely aggregates biologically distinct clinical states (e.g., PD-1–naïve vs previously PD-1–exposed disease), the near misses in the overall population should be interpreted cautiously, with particular attention to prespecified subgroup behavior and potential effect dilution. Potential confounders include differences in disease biology and baseline risk across subgroups (e.g., tumor burden/LDH, metastatic stage, immune-inflamed vs immune-excluded phenotypes, prior systemic therapy exposure, and prior adjuvant PD-1 use), all of which can influence both PD-1 sensitivity and the capacity for vaccine-driven immune augmentation. Importantly, clinical benefit was observed across nearly all predefined subgroups, with the notable exception of patients previously treated with PD-1 blockade.

In patients who were naïve to PD-1 therapy, the median progression-free survival reached 24.8 months compared with 11.0 months in the control arm, a difference that was both statistically significant and clinically substantial. This magnitude of benefit is highly consistent with the recently reported five-year follow-up of the earlier Phase II study, in which the median progression-free survival was 25 months in a cohort of 30 patients, all of whom were PD-1 naïve.²²⁴ Thus, rather than contradicting earlier findings, the Phase III results effectively confirm the Phase II efficacy signal when comparable patient populations are considered.

Prior exposure to PD-1 inhibition has been shown to drive the accumulation of dysfunctional CD38-positive T cells that are refractory to subsequent immune stimulation and cannot be efficiently rescued by vaccination.²²⁶ Consistent with this, the earlier Phase II trial also demonstrated minimal activity in PD-1 refractory patients, underscoring the biological importance of treatment sequencing.²²³ Collectively, these findings indicate that the apparent attenuation of effect size from Phase II to Phase III reflects differences in patient composition rather than loss of biological activity, and they reinforce the conclusion that IO102/IO103 may be most effective when administered in PD-1-naïve settings.^223,225,226 Together, these results establish IMVs as the first therapeutic cancer vaccine class to demonstrate an improvement in progression-free survival in metastatic disease while simultaneously highlighting their potential for transformative impact in earlier clinical settings. The combination of IO102/IO103 with PD-1 blockade has shown a uniquely favorable balance of clinical efficacy, durable immunological activity, and minimal added toxicity, with adverse events largely limited to low-grade injection-site reactions. This safety and efficacy profile strongly supports further evaluation in early-stage melanoma, where patients are uniformly PD-1 naïve, and the potential for durable immune-mediated disease control is greatest, and provides a rationale for broader exploration in other solid tumors characterized by low PD-L1 expression or immune-excluded phenotypes.

Importantly, the combined phase II and phase III clinical experience with IO102/IO103 has clarified several key principles relevant to IMV development. First, IMVs can safely expand functional anti-Tregs in patients and translate their preclinical capacity to dismantle immunosuppressive networks into durable clinical benefit. Second, the pronounced efficacy observed in PD-1 naïve patients underscores that timing and treatment sequencing are biologically decisive, with vaccination performing optimally in settings where functional T-cell priming is preserved. Third, the marked benefit in PD-L1-negative tumors demonstrates that IMVs can extend the reach of immunotherapy to patient populations that are traditionally resistant to checkpoint blockade. Collectively, these observations position IMVs as particularly well-suited for adjuvant and neoadjuvant application, where tumor burden is minimal, immune competence is preserved, and long-term administration is feasible, conditions that are likely to maximize durable therapeutic benefit. More broadly, these results mark the emergence of IMVs as a potentially transformative therapeutic class that complements and extends checkpoint blockade, with implications that reach far beyond melanoma and into the wider landscape of solid tumors. Several clinical trials are examining IDO/PD-L1-based IMV beyond melanoma. These trials in SCCHN and NSCLC have already shown encouraging activity. A phase 2 basket trial (NCT05077709)²²⁷ with the IO102/IO103 peptide vaccine in combination with anti–PD-1 in squamous cell carcinoma of the head and neck (SCCHN) and NSCLC as first-line therapy has reported encouraging results. In NSCLC (efficacy-evaluable n = 31), ORR was 48.4% (95% CI 30.2–66.9), median PFS 8.1 months (95% CI 4.2–17.7) with 18-month PFS 31% (95% CI 16–48), and median OS 22.6 months (95% CI 16.6–NE) with 18-month OS 64% (95% CI 44–78); median follow-up was 32.3 months.²²⁸ In SCCHN (efficacy-evaluable n = 18), the ORR was 44.4% (95% CI 21.5–69.2), the median PFS was 7.0 months (95% CI 2.0–13.1), the 18-month PFS was 22% (95% CI 7–43), the median OS was 22.3 months (95% CI 9.4–NE), and the 18-month OS was 61% (95% CI 35–79); the median follow-up was 23.8 months.²²⁸ No new safety signals were observed, and systemic events were consistent with pembrolizumab monotherapy.

Peptide-based vaccines are not the only IMVs being developed. Moderna is additionally pursuing an mRNA-based IMV, mRNA-4359, which encodes epitopes from IDO and PD-L1 in NSCLC and melanoma (NCT05533697).²²⁹ At ESMO 2024, early-phase results showed that mRNA-4359 monotherapy was well tolerated and induced antigen-specific T-cell responses against both IDO and PD-L1, accompanied by peripheral expansion of activated cytotoxic and memory T cells together with a reduction in Tregs and MDSCs.²²⁹ This immune-modulatory profile aligns with the characteristic IMV mechanism first demonstrated in the very first phase I study by Iversen et al. in NCSLC.²¹⁸ Updated findings presented at the 2025 ESMO meeting notably reported clinical activity in patients with checkpoint inhibitor-resistant or refractory melanoma treated with mRNA-4359 in combination with pembrolizumab, with an overall response rate of 24% and a disease control rate of 60%, and responses reached 67% in PD-L1-positive patients, where the median duration of response was not yet reached.²³⁰

Collectively, these studies illustrate that IMVs can be integrated into multiple disease settings and therapeutic combinations, with early signals of durable activity that extend beyond melanoma and provide a strong rationale for broad clinical development.

Arginase vaccination

Vaccines targeting ARG1 have also reached the clinic. Ten patients with treatment-refractory metastatic solid tumors received up to 16 subcutaneous vaccinations with three long peptides from the ARG1 hotspot region formulated in Montanide ISA-51.²³¹ The vaccine was well tolerated, with no grade 3–4 toxicities and only mild local reactions. Immune monitoring revealed vaccine-specific T-cell responses in nine of ten patients, with both CD4⁺ and CD8⁺ reactivity and production of IFN-γ and TNF-α. Although clinical activity was modest in this very late-stage setting, with transient disease stabilization in some cases, the trial demonstrated the feasibility and immunogenicity of ARG1-directed vaccination in heavily pretreated patients. A parallel phase I study extended this concept to myeloproliferative neoplasms using a dual vaccine targeting ARG1 and PD-L1.²³² Vaccination was well tolerated and elicited robust T-cell responses in all patients, with PD-L1–specific CD4⁺ and CD8⁺ T cells and ARG1-specific CD4⁺ T cells detected in peripheral blood, bone marrow, and delayed-type hypersensitivity biopsies. Peripheral profiling revealed expansion of effector CD8⁺ T-cell subsets, supporting systemic immune modulation. Although no molecular remissions were observed, these two early trials collectively establish that ARG1 is a naturally immunogenic TMA in patients and can be safely targeted by IMVs, providing a rationale for evaluation in combination with checkpoint inhibitors or in earlier disease stages where immunosuppression is less entrenched.

TGF-β vaccination

TGF-β vaccines are at an earlier stage of development but have now progressed into clinical evaluation. An ongoing trial is testing a TGF-β–based IMV in combination with radiotherapy, nivolumab, and ipilimumab in pancreatic cancer (EudraCT no. 2022-002734-13). The rationale for this approach is grounded in preclinical studies demonstrating that TGF-β–derived vaccines exert antitumor activity in desmoplastic pancreatic tumors.⁵¹ Translational analyses from the CHECKPAC clinical study, where PDAC patients were treated with radiotherapy and checkpoint blockade, further support this concept.⁶⁷ In these patients, TGF-β–specific T cells were detectable in peripheral blood prior to therapy initiation, and higher baseline reactivity against TGF-β epitopes was significantly associated with clinical benefit.⁵² Patients with spontaneous TGF-β–specific responses experienced improved progression-free and overall survival compared with those lacking detectable responses, while nonresponders did not display evidence of generalized immune impairment. These observations support baseline TGF-β–specific T-cell reactivity as a candidate stratification biomarker for TGF-β–axis combinations, which now requires prospective validation with harmonized epitope panels and assay readouts before clinical implementation. If confirmed, baseline reactivity could be used to enrich for patients most likely to benefit from TGF-β–directed IMVs in desmoplastic/immune-excluded settings.

Overall, these findings demonstrate that natural immunity to TGF-β exists in pancreatic cancer patients and can stratify individuals most likely to benefit from immunotherapy, thereby providing a compelling rationale for advancing TGF-β–directed vaccines into clinical development.

Survivin and VEGF/VEGFR vaccines

Survivin has been known as a TAA antigen for 25 years,¹¹⁷ and has been the subject of several clinical trials. In a case report of a patient with gemcitabine-refractory pancreatic cancer, repeated vaccination with an HLA-A2–restricted survivin peptide induced strong survivin-specific T-cell responses and led to partial and subsequently complete remission of liver metastases lasting eight months before disease recurrence after cessation of therapy.²³³ Building on this, a phase II trial in patients with treatment-refractory stage IV melanoma evaluated survivin-derived peptides restricted to HLA-A1, HLA-A2, or HLA-B35. The vaccine was safe and immunogenic, and the induction of survivin-specific T-cell reactivity correlated with clinical outcome.¹⁹³ Patients mounting vaccine-induced responses had a significantly longer overall survival than nonresponders (median 19.6 vs. 8.6 months), and multivariate analysis confirmed survivin-specific immunity as an independent predictor of survival. Survivin-directed vaccine programs have progressed into clinical development across multiple tumor types. Maveropepimut-S (DPX-Survivac) is currently under investigation in indications including ovarian cancer and diffuse large B-cell lymphoma (DLBCL).²³⁴ SurVaxM, developed by MimiVax, is a survivin mimic peptide vaccine that has been evaluated primarily in glioblastoma but has broader applicability across cancers.²³⁵

Whereas survivin-based vaccines have primarily focused on targeting tumor cell expression, VEGF- and VEGFR-directed vaccines have provided additional evidence of antiangiogenic activity in clinical trials. VXM01, an oral Salmonella typhi-based vaccine encoding VEGFR2, was evaluated in a randomized phase I trial in advanced pancreatic cancer and was shown to be safe with manageable adverse events. Approximately half of the boosted patients developed sustained VEGFR2-specific T-cell responses, and vaccination was associated with transient vascular modulation consistent with an antiangiogenic mechanism, supporting the feasibility of prime/boost VEGFR2-directed immunotherapy.²³⁶ Another VEGF-based vaccine, CIGB-247, was tested in a phase I trial in 30 patients with advanced solid tumors.²³⁷ This vaccine was safe, elicited both anti-VEGF antibodies and T-cell responses, and long-term reimmunization remained well tolerated. Clinical benefit was observed in 12 patients, including two complete responses, and several patients survived beyond 20 months, providing a strong rationale for further clinical development of VEGF-targeted vaccination strategies.

Safety and tolerability of immune-modulatory vaccines across clinical settings

Because IMVs intentionally expand self-reactive T-cell populations, careful evaluation of safety is essential, particularly with respect to immune-related adverse events, organ-specific toxicity, and long-term risk. Across preclinical models and clinical trials conducted to date, IMVs have consistently demonstrated a favorable safety and tolerability profile.

In the first clinical trial of IDO-based vaccination in NSCLC, two patients continued vaccinations every four weeks for more than five years without evidence of cumulative toxicity, autoimmune manifestations, or organ-specific adverse events while maintaining durable IDO-specific T-cell responses.²¹⁹ Similarly, in a study of ten patients with multiple myeloma, repeated PD-L1-based vaccination administered up to fifteen times over one year was well tolerated, induced PD-L1-specific T-cell responses in all participants, and was associated primarily with mild grade I to II injection-site reactions, with no reported immune-mediated organ toxicity.²²⁰ Importantly, no treatment-related endocrinopathies, colitis, pneumonitis, hepatitis, or neurologic adverse events were observed in these early studies.

When IMVs were combined with anti–PD-1 therapy, the overall toxicity profile closely resembled that of checkpoint blockade alone, without an increased incidence or severity of immune-related adverse events.^42,222 This observation suggests that IMVs do not broadly amplify systemic autoimmunity but rather act in a spatially and antigen-restricted manner. Consistent with this, adverse events reported in the recent phase III melanoma trial were largely limited to transient injection-site reactions, with no new safety signals emerging during extended follow-up.²²⁵ Nevertheless, rare or delayed tissue-specific autoimmune events may not be fully captured in early-phase studies, particularly as IMV programs move into earlier-stage settings with longer treatment durations and broader antigen coverage. Therefore, continued long-term follow-up with systematic capture of organ-specific immune-related adverse events (e.g., endocrine, gastrointestinal, hepatic, pulmonary, dermatologic, and neurologic) remains essential.

Long-term safety is further supported by multiple in vivo studies demonstrating that sustained expansion of anti-Tregs does not result in spontaneous autoimmunity or tissue damage, even under conditions of repeated vaccination.^42,51,211 The spontaneous presence of anti-Tregs in healthy individuals, as described earlier in this review, provides an additional physiological rationale for the observed tolerability of IMVs.

Taken together, the available data indicate that IMVs can expand anti-Tregs and remodel suppressive immune circuits without inducing systemic immune dysregulation. This favorable safety profile, including the absence of cumulative toxicity during long-term administration, supports further clinical development of IMVs in adjuvant and neoadjuvant settings, where prolonged vaccination schedules and preservation of immune function are critical for preventing recurrence and establishing durable immune control. At the same time, continued long-term monitoring in larger patient cohorts will be essential to fully define rare or delayed immune-related risks as these strategies move into earlier disease stages.^{42,51,211,219,220,222,225}

IMV vaccine platforms

IMVs can be developed through multiple vaccine platforms, each associated with distinct advantages and limitations with respect to immunogenicity, safety, durability of response, and scalability, thereby offering diverse opportunities to optimize efficacy across clinical settings.⁷¹ Peptide-based vaccines have thus far been the most widely explored, with long peptides targeting IDO, PD-L1, ARG1, and TGF-β demonstrating excellent safety, induction of antigen-specific T cells, and feasibility of long-term repeated dosing without systemic autoimmunity. Emulsions from the Montanide family, most frequently Montanide ISA-51, have been the primary adjuvants used in these trials, creating a depot effect and sustaining antigen release.^{218,221,222,238,239} Looking forward, the incorporation of additional immunostimulatory adjuvants such as poly-ICLC or other TLR agonists may further enhance immunogenicity and drive vaccine-induced T cells toward a more proinflammatory phenotype.²⁴⁰ A potential limitation of peptide-based IMVs is the requirement for repeated administration and, in some cases, HLA restriction, which may necessitate careful patient selection. The latter can be mitigated by the use of long peptides containing multiple epitopes.

RNA-based vaccines represent a particularly flexible platform capable of encoding multiple TMA epitopes within a single construct while simultaneously engaging innate immune pathways. Recently, a study evaluated an mRNA–LNP IMV encoding a polyepitope construct targeting multiple TMAs, i.e., CCL22, TGF-β, galectin-3, PD-L1, IDO1, and ARG1, in canines.²⁴¹ In this pilot trial in dogs with spontaneous cancers, the vaccine was well tolerated with only mild adverse events and achieved a 75% disease control rate, with sustained stable disease across multiple tumor types. These findings supported the feasibility of a multiantigen IMV approach and indicated that broad targeting of TMAs could provide meaningful clinical benefit in a translationally relevant setting. However, RNA-based platforms may be associated with increased innate immune activation and logistical challenges related to formulation, storage, and distribution, which require careful optimization in clinical development.

The clinical potential of mRNA-based vaccines for cancer immunotherapy has been highlighted in the Moderna melanoma trial, where an mRNA cancer vaccine reduced recurrence risk when combined with PD-1 blockade.²⁴² Within the IMV field, an mRNA format encoding IDO and PD-L1 epitopes²²⁹ has been described as advancing into clinical testing, illustrating how this platform can be adapted to expand anti-Treg immunity and complement checkpoint inhibitors.

DNA-based vaccines have still not entered the clinical stage for IMVs but provide compelling advantages for future development.²⁴⁰ They are cost-effective, thermostable, and suitable for scalable manufacturing, and clinical experience in other tumor types, such as HPV-associated cancers, has confirmed their immunogenicity and early clinical activity. These attributes position DNA vaccines as a promising next-generation modality for IMVs once optimized for regulatory antigens. The main limitation of DNA-based vaccines remains the need for optimized delivery and sufficient in vivo transfection efficiency, which has thus far delayed their entry into IMV-specific clinical testing.

Taken together, the choice of platform will depend on the clinical setting, the TMAs targeted, and the desired balance between immune potency, durability, safety, manufacturing complexity, and scalability.

Peptide vaccines provide strong immunostimulatory capacity and an established safety record, RNA vaccines offer flexibility, and DNA vaccines bring stability and cost-effective scalability.²⁴⁰ The ability to tailor IMV design across these platforms ensures a dynamic field with significant potential for innovation and clinical impact.

From a translational perspective, platform choice can be framed along three dimensions. Immunogenicity differs by platform. Long-peptide IMVs depend on adjuvant-driven priming and repeated boosting. They have shown robust antigen-specific T-cell induction and a well-established safety profile. mRNA/LNP platforms enable multiepitope encoding and can engage innate sensing. This may increase potency. Scalability and logistics also differ. Peptides benefit from mature GMP workflows and simple outpatient administration. mRNA platforms introduce formulation constraints and cold-chain requirements. DNA vaccines offer thermostability and cost-effective manufacturing. However, efficacy can be limited by delivery and in vivo transfection efficiency. Clinical applicability depends on context. Peptide IMVs fit prolonged dosing and maintenance paradigms. mRNA platforms may be preferable when broader multi-TMA coverage is needed to address heterogeneity. DNA approaches could support scalable repeated boosting once delivery is optimized.

Clinical summary

Clinical experience to date confirms several of the central principles first established in preclinical models. TMAs are naturally immunogenic, and vaccination against them can safely expand functional anti-Tregs in patients, leading to remodeling of suppressive cell populations, reduction of fibrosis, modulation of angiogenesis, and synergy with immune checkpoint blockade. The phase III trial of the IO102/IO103 peptide vaccine in advanced melanoma provided the first evidence that therapeutic vaccination can improve progression-free survival in metastatic cancer, thereby establishing IMVs as a distinct class of immunotherapy.

At the same time, accumulated clinical data highlight important contextual limitations that must be considered when interpreting these results. Many early IMV trials were conducted in heavily pretreated patients with advanced disease, where profound immune dysfunction, T-cell exhaustion, and entrenched stromal suppression are likely to constrain the magnitude and durability of vaccine-induced immune responses. In these settings, immune activation has often been measurable and biologically meaningful but is not always sufficient as monotherapy to induce deep or durable tumor regression. These observations underscore that the clinical efficacy of IMVs is highly context dependent and influenced by disease stage, immune competence, and treatment sequencing.

With basket trials underway across multiple tumor types and adjuvant and neoadjuvant studies progressing in melanoma and head and neck cancer, the clinical scope of IMVs continues to broaden. This broader need for strategies that remodel suppressive microenvironments is also reflected in contemporary disease-focused immunotherapy overviews, including recent syntheses in gastric cancer.²⁴³ In parallel, the introduction of novel delivery platforms such as mRNA and DNA vaccines underscores the adaptability of the IMV approach and provides additional opportunities to enhance immunogenicity. An additional priority is the development of predictive biomarkers beyond PD-L1 expression, including baseline immune reactivity, cytokine signatures, and stromal features, to identify patients most likely to benefit and to guide rational integration with other immunotherapies. A practical biomarker roadmap for IMVs is best framed by intended use rather than by a single universal marker, since performance will depend on target, indication, disease stage, and combination partner. At present, most IMV-associated biomarkers should be regarded as candidate predictors supported by correlative analyses and require prospective validation with prespecified hypotheses and harmonized assays before routine clinical deployment. In the near term, clinically actionable stratifiers are likely to include treatment history and disease context (e.g., PD-1–naïve versus PD-1–exposed disease and earlier versus late-stage/high-burden settings), which can act as major effect modifiers of vaccine-mediated immune augmentation. A second tier comprises mechanism-linked candidate predictors, including baseline TMA-specific immune reactivity and features reflecting suppressive stromal biology (e.g., immune-exclusion and TGF-β–associated programs) that may identify patients most capable of vaccine amplification. Finally, early on-treatment pharmacodynamic readouts (e.g., induction of defined cytokine/chemokine signatures and expansion of vaccine-reactive T-cell responses) may be most informative for optimizing sequencing and tailoring combination strategies.

Optimal IMV dosing schedules are likely to be context dependent. They will vary with target biology, platform, disease stage, and combination partner. Nevertheless, current clinical experience demonstrates the feasibility of repeated and prolonged dosing. PD-L1–based peptide vaccination has been administered up to 15 times over one year, and IDO vaccination has been continued at four-week intervals for years in selected patients, without cumulative toxicity. Similar prolonged dosing feasibility has been reported with other peptide IMVs. These data support development paradigms that combine an initial priming phase with subsequent maintenance boosting, particularly in clinically stable adjuvant/neoadjuvant settings where treatment windows allow coordinated priming and boosting. Future trials should define the minimal priming intensity and optimal boosting interval using standardized immunomonitoring (magnitude, durability, and functional quality of TMA-specific responses) and should align vaccination timing with combination partners such as checkpoint blockade. Heterologous prime–boost approaches enabled by platform diversity may further increase magnitude and breadth but remain insufficiently studied within IMVs and warrant prospective evaluation.

These considerations indicate that the future clinical impact of IMVs will depend on both strengthening the magnitude and quality of IMV-induced immune responses and optimizing the biological context in which they are applied. Accordingly, two complementary strategies emerge as central to the continued development of IMVs. First, rational combination strategies will likely be required to amplify and sustain IMV-induced immune activity, particularly through integration with immune checkpoint blockade, radiotherapy, or other immune-modulating interventions. These approaches are discussed in detail in the “Combination strategies” section, which focuses on combination strategies involving IMVs. Second, there is a strong biological rationale for deploying IMVs earlier in the disease course, where immune competence is greater, tumor burden is lower, and suppressive networks are less established. The expansion of IMVs into adjuvant and neoadjuvant settings and their potential role in early-stage disease are addressed in the “Expanding clinical applications into earlier disease stages” section. Together, these directions define the next phase of IMV development and provide a coherent framework for the sections that follow.

Combination strategies

The design of IMVs must take into account the distinct repertoire of TMAs, which reflects the evolving phenotype and functional state of the TME (Fig. 6). In inflammatory contexts, TMAs such as PD-L1 and IDO are frequently upregulated as counterregulatory responses designed to suppress immune activity. In the setting of a TMA-based vaccine, however, these upregulated molecules serve as targets for TMA-specific T cells, and their recognition can amplify inflammation and sustain a proinflammatory shift within the microenvironment. Indeed, preincubation of target cells with IFN-γ increases their susceptibility to recognition by IDO- and PD-L1–specific T cells.^36,44 This principle is also relevant for tumors that are initially noninflamed but enriched for suppressive populations such as TAMs, MDSCs, or CAFs, which may express high levels of ARG1 or TGF-β (Fig. 6). In such cases, an ARG1- or TGF-β-based vaccine can activate specific T cells that, through cytokine production, reprogram suppressive populations and render them more vulnerable to further attack by IDO- and PD-L1-specific T cells. These mechanisms support the rationale for combining multiple TMAs in vaccine formulations, since cocktails of antigens may produce synergistic effects.⁷⁴

Fig. 6 — Tailoring IMVs to the dynamics of the TME. Schematic representation of an immune cell, such as a TAM, expressing and presenting distinct TMAs, shaped by the characteristics of the TME. Cells within the TME express different TMAs depending on whether the tumor is inflamed or noninflamed. Consequently, the same cell type can be recognized by different TMA-specific T cells. For example, TMAs such as IDO and PD-L1 are predominantly expressed in inflamed tumors, such as melanoma, while ARG1 and TGF-β are more commonly found in noninflamed or “cold” tumors, such as pancreatic cancer. Therefore, the selection and combination of TMAs for IMVs should be tailored to the tumor type and based on the patient’s specific TME profile. The figure was created with BioRender.com

The rationale for combining IMVs with other anticancer therapies is compelling, as IMVs act not only by expanding effector T cells but also by dismantling immunosuppression at its cellular source. IMVs remove a major barrier that limits the effectiveness of subsequent immune-based or cytotoxic therapies. Evidence from both mechanistic studies and translational research reinforces this principle, showing that IMVs can convert a hostile and immune-excluded TME into one that is permissive and inflamed, thereby enhancing the activity of checkpoint inhibitors, tumor-antigen vaccines, adoptive cell therapies, and conventional anticancer treatments. Looking forward, IMVs are poised to serve as synergistic platforms that not only potentiate existing therapies but also extend immunotherapy benefits to patient populations and tumor types that have historically remained unresponsive. The following subsections will review the most important avenues of clinical translation, focusing on combinations with checkpoint inhibitors, cancer vaccines, adoptive cell therapies, and standard oncologic modalities.

IMVs with checkpoint inhibitors

As described above, the most advanced combination strategy for IMVs is PD-1 blockade, and this pairing has now progressed from preclinical proof-of-concept to pivotal clinical trials. As discussed earlier, IMVs complement checkpoint inhibition by addressing two barriers simultaneously. The combination of IMVs with checkpoint inhibitors would thus be expected to increase the proportion of patients who respond to therapy,²²² particularly since checkpoint blockade demonstrates its highest efficacy in inflamed, or “hot,” tumors.¹⁵² While ICIs release the brakes on preexisting tumor-reactive lymphocytes, they are ineffective in tumors with sparse T-cell infiltration or those dominated by myeloid and stromal suppression. IMVs counter these limitations by expanding new effector clones against TMAs and eliminating or reprogramming the suppressive cells that enforce resistance.

The failure of phase III trials with small-molecule IDO inhibitors, most notably the ECHO 301 KEYNOTE 252 study combining epacadostat with pembrolizumab, demonstrated that pharmacologic blockade of IDO enzymatic activity alone is insufficient to improve clinical outcome. In contrast, IDO directed IMV functions by inducing adaptive immune responses through expansion of IDO-specific CD4 and CD8 T cells that target IDO-expressing suppressive cells within the tumor microenvironment, induce local inflammation, and establish immunological memory, thereby highlighting a fundamental mechanistic difference between metabolic inhibition and IMV. These mechanistic insights translated directly to the clinic and back. In the first-line phase II melanoma trial, IDO-PD-L1 vaccine-induced T cells were detectable in blood and tumor tissue, where biopsies revealed myeloid repolarization and a proinflammatory shift.²²² Functional assays confirmed that vaccine-expanded clones recognized autologous myeloid cells conditioned by melanoma, demonstrating that IMVs act directly within the suppressive tumor niche. Mechanistic work provided further validation of this synergy. Using patient-derived material, PD-L1–specific T cells induced by IO102/IO103 were shown to directly recognize and reprogram PD-L1⁺ CD14⁺ myeloid cells.²⁴⁴ This interaction reversed their suppressive phenotype, enhanced antigen presentation, altered cytokine and chemokine production, and boosted the cytotoxic function of tumor-infiltrating lymphocytes. These findings demonstrate that IMVs not only expand antigen-specific T cells but also rewire suppressive myeloid compartments, offering a mechanistic explanation for their strong clinical synergy with PD-1 blockade. The phase III trial further validated this synergy, as the phase III trial of IO102/IO103 plus pembrolizumab achieved the longest progression-free survival reported in melanoma to date, establishing therapeutic vaccination as a clinically effective strategy in metastatic disease.²²⁵ The same logic extends to IMVs targeting metabolic and cytokine pathways such as ARG1 and TGF-β, where preclinical data point to strong complementarity with checkpoint inhibition.⁴² ARG1 vaccination reduces suppressive MDSCs, restores effector proliferation, and delays tumor growth. By dismantling both metabolic suppression and structural barriers, ARG-directed IMVs establish conditions in which ICIs can sustain deeper and more durable responses. TGF-β vaccination acts through a different but equally synergistic mechanism. In pancreatic and colorectal cancer models, TGF-β–specific T cells reduced fibrosis, reprogrammed CAFs, and enhanced infiltration of CD8⁺ and NK cells.⁵¹ Importantly, translational analyses from the CheckPAC trial⁶⁷ demonstrated that PDAC patients with baseline TGF-β–specific immunity had significantly improved survival when treated with radiotherapy and checkpoint blockade.⁵² Together, these findings establish that targeting stromal and cytokine TMAs not only remodels the microenvironment directly but also amplifies the effectiveness of checkpoint inhibition.

Dual checkpoint blockade is moving forward as a novel treatment option in advanced cancers. First, nivolumab (anti–PD-1) plus ipilimumab (anti–CTLA-4) demonstrated durable and clinically meaningful benefits in advanced melanoma.^245,246 In the phase 3 CheckMate 067 trial, the combination significantly prolonged overall survival compared with ipilimumab alone, with a hazard ratio for death of 0.55 at three years and 0.52 at five years. The median overall survival exceeded 60 months at five years, compared with 37.6 months for nivolumab monotherapy and 19.9 months for ipilimumab. The overall survival rates at five years were 52%, 44%, and 26%, respectively. These data established nivolumab plus ipilimumab as a standard for advanced melanoma, demonstrating a long-term benefit that is sustained over half a decade. However, the improved efficacy was accompanied by increased immune-related toxicity, with grade 3–4 adverse events in nearly 60% of patients on the combination compared with approximately 20–30% in the monotherapy groups.

Preclinical and early clinical data provide a strong biological rationale for combining this dual checkpoint blockade with IMVs. The simultaneous inhibition of CTLA-4 and PD-1 enhances vaccine efficacy by activating and expanding cytotoxic T cells while reducing regulatory T-cell accumulation within the TME. Mechanistically, dual CTLA-4 and PD-1 blockade targets distinct regulatory pathways, producing additive and often synergistic effects when combined with vaccination. In murine models of colon carcinoma and melanoma, the combination of checkpoint inhibitors with cellular vaccines significantly enhanced antitumor activity, increased the frequency of intratumoral effector T cells, and reduced Tregs, providing a strong rationale for clinical translation.⁵⁷ In another study, a PLG–based cancer vaccine administered with anti–CTLA-4 or anti–PD-1 antibodies enhanced cytotoxic T-cell responses, induced regression of established B16 tumors, and achieved survival rates of 75%, demonstrating potent synergy between material-based vaccination and checkpoint blockade.²⁴⁷ Similarly, a synthetic hTERT DNA vaccine combined with CTLA-4 or PD-1 inhibition improved antitumor efficacy.²⁴⁸ Together, these data suggest that combining IMVs with this dual checkpoint blockade represents a particularly powerful therapeutic strategy. CTLA-4 inhibition may act as an immune adjuvant that strengthens T-cell priming and expands vaccine-induced anti-Treg populations directed against TMAs, while concurrent PD-1 blockade sustains the activity of these effector cells within the tumor. This coordinated modulation of priming and effector phases is expected to induce inflammation and remodeling of the TME, enabling deeper and more durable responses to immunotherapy.

More recently, dual inhibition of PD-1 and LAG-3 has emerged as an effective and less toxic alternative to combined PD-1 and CTLA-4 blockade.²⁴⁹ In a global phase 2–3 trial in previously untreated metastatic melanoma, the combination of relatlimab, an anti–LAG-3 antibody, with nivolumab extended median progression-free survival to 10.1 months compared with 4.6 months for nivolumab alone (hazard ratio 0.75; P = 0.006). The benefit was consistent across major clinical subgroups.²⁴⁹ Integrating IMVs into this dual checkpoint framework is supported by several complementary mechanistic insights. LAG-3 negatively regulates T-cell activation, maintaining immune homeostasis under physiological conditions but contributing to immune escape within the TME. Blockade of LAG-3 restores effector T-cell function while simultaneously limiting Treg-mediated suppression. Because antitumor vaccination increases the expression of multiple checkpoint receptors on activated CD8⁺ T cells, including PD-1 and LAG-3, combining vaccines with checkpoint inhibitors enhances efficacy by synchronizing antigen-specific priming with sustained effector function. In murine models, vaccination combined with PD-1 or LAG-3 blockade improved tumor control, while the simultaneous inhibition of both checkpoints produced the strongest therapeutic effect, particularly in the MycCaP prostate cancer model, where PD-1 inhibition alone was insufficient.²⁵⁰ These findings indicate that vaccines may achieve maximal efficacy when paired with dual blockade of PD-1 and LAG-3, which are upregulated during vaccine-induced T-cell activation. Hence, engineered heteroclitic BCMA peptides induced potent BCMA-specific CD8⁺ T cells with enhanced activation, costimulatory signaling, and polyfunctional Th1-type activity. Treatment of these vaccine-activated BCMA-specific cytotoxic T lymphocytes with anti–LAG-3 further augmented their immune function, demonstrating that LAG-3 blockade can potentiate vaccine-induced, antigen-specific T-cell responses and support durable antimyeloma immunity.²⁵¹ Antigenic stimulation reprogrammed dysfunctional CD8⁺ T cells, re-establishing antigen sensitivity and synergizing with checkpoint inhibition to produce functional tumor-eliminating CD8⁺ T cells without provoking further autoimmunity.²⁵² Together, these findings provide a strong biological foundation for integrating IMVs with dual PD-1 and LAG-3 blockade. IMVs may enhance the priming of anti-Treg and effector responses directed against TMAs, while checkpoint inhibition maintains effector activity within the tumor. This interplay is expected to promote inflammation, myeloid reprogramming, and immune infiltration, thereby improving tumor control. Consistent with this rationale, an investigator-initiated study at Memorial Sloan Kettering Cancer Center is evaluating the combination of IO102/IO103 with nivolumab and relatlimab in advanced melanoma (NCT05912244). This trial directly tests whether IMVs can amplify the therapeutic efficacy of dual checkpoint inhibition.

The clinical experience with dual immune checkpoint inhibition has shown that efficacy gains come at the cost of substantially increased toxicity, establishing a practical ceiling for further escalation with additional ICIs. IMVs offer a means to enhance the efficacy of existing ICIs without compounding immune-related adverse events, making them an ideal partner for combination therapy.

IMVs with tumor-antigen vaccines

An attractive avenue for IMV development is their combination with traditional cancer vaccines, including tumor-associated antigen-based vaccines and tumor-specific neoantigen vaccines.¹²⁶ While neoantigen vaccines are designed to amplify highly specific effector T-cell responses against mutated tumor antigens, IMVs operate through a complementary mechanism by dismantling suppressive networks within the tumor microenvironment. It can therefore be anticipated that IMVs will synergize with this therapeutic class and that the addition of TMAs to the antigen repertoire of established vaccine platforms represents a straightforward and practical strategy. Conventional tumor-antigen vaccines, whether peptide-based, dendritic-cell–based, DNA, or RNA, are expected to perform more effectively in a TME that has been inflamed and desuppressed by IMVs.²⁵³ IMVs may thus establish conditions that are more permissive for priming, infiltration, and persistence of tumor-antigen–specific effector T cells. This immunological conditioning is particularly relevant for personalized neoantigen vaccines, whose efficacy depends on efficient priming, intratumoral trafficking, and sustained function of low-frequency T-cell clones. Preclinical and translational studies provide consistent evidence for this synergy. In vitro IDO- or PD-L1–specific anti-Tregs enhanced the function of viral and tumor-antigen–specific T cells, including influenza- and MART-1–reactive clones, by releasing them from suppression.^{36,45–47,69} Incorporation of a PD-L1–derived peptide into dendritic-cell vaccines augmented both the magnitude and quality of antigen-specific responses in vitro, demonstrating that TMAs can be layered onto existing vaccine platforms to increase immunogenicity.^90,104 In murine models, co-vaccination with an IDO-based IMV and tumor-antigen vaccines such as gp100 resulted in superior tumor control compared with antigen vaccination alone.²¹² The combined strategy expanded and activated antigen-specific CD8⁺ T cells, increased their intratumoral infiltration, and reduced the abundance of suppressive IDO⁺ MDSCs and dendritic cells. Mechanistically, the benefit of adding TMAs to traditional cancer vaccines arises from the ability of IMVs to dismantle regulatory bottlenecks that constrain tumor-antigen vaccination. By eliminating IDO⁺ or PD-L1⁺ suppressive cells, IDO- and PD-L1–based IMVs restore antigen presentation, promote IL-12 production, and shift the cytokine milieu toward a proinflammatory state. Long-peptide IMVs further amplify this effect by stimulating both CD4⁺ and CD8⁺ compartments, thereby coupling the cytotoxic elimination of suppressive populations with helper responses that drive cross-priming and epitope spreading. In this context, IMVs can be viewed as enabling vaccines that convert immune-excluded or suppressed tumors into environments where neoantigen-directed and other tumor-antigen-specific T-cell responses can be effectively unleashed, including in combination with PD-1 blockade. Taken together, these findings indicate that IMVs can be readily integrated into existing cancer vaccine strategies.

IMVs with cellular therapies

Adoptive cell therapies (ACTs), including TIL therapy, engineered TCRs, and CAR-T cells, have transformed the treatment of hematological malignancies, with CD19-directed CAR-T cells achieving durable remissions in B-cell cancers,²⁵⁴ and BCMA-directed,^255,256 CAR-T cells now approved for multiple myeloma. In solid tumors, progress has been slower, but encouraging signals are emerging. TIL therapy has demonstrated clinically meaningful benefit and was recently approved for advanced melanoma, while engineered CAR-T and TCR therapies targeting antigens such as mesothelin²⁵⁷ and MAGE-A4²⁵⁸ have shown activity in early-phase trials. Nevertheless, the broader application of ACT in solid tumors remains constrained by tough challenges,²⁵⁴ including inefficient trafficking into tumor sites, survival in metabolically hostile niches, and resistance driven by suppressive myeloid and stromal compartments.²⁵⁴ As previously discussed, IMVs address these barriers. These changes convert immune-excluded tumors into accessible lesions, improve the homing and dwell time of infused cells, and restore CD4⁺. Vaccination against enzymes such as ARG1 or IDO also alleviates nutrient deprivation, further supporting ACT persistence and function. Although clinical data are not yet available, the preclinical data described here suggest that IMVs are purpose-built adjuncts for cellular therapy in solid tumors.

A novel strategy is now extending this rationale into the design of engineered TCR-T cells directed against TMAs themselves.²⁵⁹ Recent work has described the generation of PD-L1-specific TCR-T cells (PDL101-TCR) derived from naturally occurring PD-L1–reactive T cells and optimized through CRISPR-Cas9 knock-in technology. These engineered cells exhibit potent, antigen-dependent cytotoxicity against both PD-L1⁺ tumor cells and immunosuppressive immune subsets within the TME while maintaining a recognition threshold that may provide a safer therapeutic profile than PD-L1–directed CAR-T cells. Importantly, this platform establishes a direct cellular therapy approach targeting immunoregulatory pathways that IMVs were originally designed to engage. The integration of IMVs with such engineered TCR-T strategies provides a compelling bidirectional opportunity. IMVs encoding the same TMA (for example, PD-L1) can be administered after TCR-T infusion to sustain and expand the engineered clones in vivo, thereby ensuring their persistence and functionality. Conversely, the infused TCR-T cells provide an immediate effector pool that can be further amplified and supported by the vaccine. This dual approach unites the durability of vaccination with the direct cytotoxic potential of TCR-T cells, offering a blueprint for future combined strategies in which IMVs and cellular therapies cooperate to remodel the TME and achieve durable tumor control.

IMVs with chemotherapy and radiotherapy

Chemotherapy and radiotherapy promote the release of tumor antigens, increase HLA expression, and generate danger-associated molecular patterns that can prime T-cell immunity. At the same time, these treatments often provoke a rebound of immunosuppressive pathways and fibrosis, which restore tolerance and limit the durability of therapeutic effects, but at the same time increase the local expression of TMAs. IMVs are uniquely designed to prevent this rebound by eliminating or reprogramming the suppressive cells that sustain tolerance, thereby maintaining an inflamed TME and ensuring that immunogenic cell death translates into productive antitumor immunity.

The IDO pathway illustrates this rationale clearly.^77,260–263 Small-molecule IDO inhibitors have been shown to cooperate with chemotherapy in vitro and induce regression of tumors otherwise resistant to single-agent therapy, in part by preventing transformed cells from escaping T-cell-dependent immune surveillance. By stabilizing the immune landscape after chemotherapy, IDO-targeted IMVs represent a strategy to combine the antigen-releasing effects of cytotoxic therapy with protection against the immunosuppressive rebound that typically follows. The ARG pathway provides another compelling example.^264,265 ARG-directed IMVs can correct metabolic suppression and soften fibrotic barriers, making them attractive partners for chemotherapy and radiotherapy. Chemotherapy itself can synergize with checkpoint inhibition by enhancing antigen release and priming immunity, but this effect is often limited by concurrent increases in PD-L1 expression on tumor and stromal cells.²⁶⁶ Vaccination against PD-L1 may generate T cells that directly counteract the PD-L1 upregulation induced by chemotherapy, effectively turning a common resistance mechanism into a therapeutic opportunity. PD-L1-directed IMVs may thereby complement chemo–ICI combinations and ensure that chemotherapy-induced antigen release is not neutralized by PD-L1–mediated tolerance. This integration provides a rationale for evaluating PD-L1 vaccines alongside combined cytotoxic and checkpoint blockade regimens.^{184,189,267–269}

The TGF-β axis highlights perhaps the clearest example of synergy between IMVs and radiotherapy (Fig. 7). Radiotherapy is a cornerstone of cancer care, received by approximately 50% of patients during the course of their disease.²⁷⁰ Its therapeutic effects extend beyond direct cytotoxicity, as it induces immunogenic cell death that releases tumor antigens and inflammatory signals.⁶⁷ These immune-activating features provide a rationale for combining radiotherapy with immunotherapies, and abscopal effects demonstrate that radiotherapy can trigger systemic antitumor responses even at distant lesions.^159,271 However, radiotherapy simultaneously initiates tissue repair programs that increase TGF-β expression, a cytokine that drives immunosuppression, fibrosis, and immune exclusion.^64,156 Elevated TGF-β is a well-recognized driver of resistance to both checkpoint blockade and radiotherapy, underscoring the need for strategies that counteract this axis.

In preclinical models, TGF-β vaccination increased CD8⁺ T-cell infiltration, shifted macrophage polarization toward proinflammatory states, and reduced collagen deposition and CAF-associated gene expression, thereby remodeling the fibrotic stroma.^51,70,163 Importantly, spontaneous baseline immunity against TGF-β correlated with improved outcomes in pancreatic cancer patients treated with radiotherapy and checkpoint blockade.⁵² In a randomized phase II trial of pancreatic cancer, patients with preexisting TGF-β–specific T cells achieved significantly longer progression-free and overall survival when treated with radiotherapy plus ICIs, strongly suggesting that TGF-β-directed vaccination can convert radiotherapy-induced immune activation into durable clinical benefit.

Taken together, these findings suggest that IMVs are well-suited for integration with chemotherapy and radiotherapy. They prevent the suppressive rebound that follows cytotoxic treatment, reprogram the stromal and metabolic environment, and provide proinflammatory support that amplifies the immunogenic potential of cytotoxic therapy. Nonetheless, important questions remain unresolved, particularly concerning optimal scheduling. Cytotoxic therapies primarily target proliferating cells, and vaccination itself induces clonal expansion and proliferation of effector T cells. Determining how to best time IMV administration relative to chemotherapy or radiotherapy will therefore be critical to maximize efficacy while minimizing inadvertent depletion of vaccine-induced effector populations. Addressing these issues in translational studies and early clinical trials will be essential to fully harness the potential of IMV–cytotoxic therapy combinations.

Summary of combination rationale

Together, these data demonstrate that IMVs are powerful amplifiers of other therapeutic modalities. By targeting suppressive cells directly, IMVs lift bottlenecks that constrain checkpoint inhibitors, tumor-antigen vaccines, adoptive cell therapies, and standard cytotoxics. The consistent theme is that IMVs convert hostile, immune-excluded microenvironments into permissive microenvironments. Their mechanism is distinct but complementary to existing modalities, and their favorable safety profile makes them ideally suited for integration into multimodality therapy.

Expanding clinical applications into earlier disease stages

The clinical development of IMVs has thus far been concentrated in advanced and metastatic disease, yet experience from both IMVs and other therapeutic cancer vaccine platforms increasingly points to earlier disease stages as a very promising setting.²⁷² Evidence from neoantigen and other therapeutic vaccine studies demonstrates that patients with lower tumor burden, preserved immune repertoires, and less therapy-induced immunosuppression are most likely to mount durable antitumor responses. These principles apply to IMVs, which combine an excellent safety profile, sustained immunogenicity, and a mechanism of action that makes them particularly well-suited for adjuvant and neoadjuvant use.

The earliest IMV trials were conducted in heavily pretreated patients with advanced malignancies and established the essential foundation of safety and immunogenicity required for translation into earlier settings.⁷³ Across multiple IMV targets and clinical trials, these results have been consistent.^{150,219–221,232,238} In addition, ongoing TGF-β peptide vaccination in advanced pancreatic tissue has proven feasible and immunogenic (unpublished), and Survivin and VEGF/VEGFR vaccines further confirmed that stromal and angiogenic TMAs can be targeted without compromising safety.^193,273 The phase III melanoma trial with an IDO/PD-L1–based IMV subsequently extended these findings, particularly in anti–PD-1–naïve patients,²²⁵ underscoring both the clinical validity of the IMV approach and its potential value in earlier disease settings.

Adjuvant setting

Following surgical resection, the overall tumor burden is minimized, yet micrometastatic disease and residual immunosuppressive niches often persist as the principal drivers of relapse. The rationale for IMVs in the adjuvant setting is compelling. Conventional adjuvant therapies reduce recurrence risk but at the expense of systemic toxicity. In contrast, IMVs offer a safe and immune-activating strategy compatible with long-term administration, capable of dismantling suppressive compartments such as MDSCs, CAFs, and Tregs that persist after resection. By eliminating these cell types or reprogramming them into proinflammatory states, IMVs directly target the mechanisms that promote recurrence while avoiding the toxicity of cytotoxic or prolonged systemic therapies.

Support for deploying IMVs at this stage is further strengthened by experience with other therapeutic cancer vaccines, which have yielded important biological and clinical insights.⁷¹ A consistent finding across studies is that vaccination is most effective in patients with low tumor burden and preserved immune competence, where effector repertoires remain intact, and the risk of T-cell exhaustion from chronic antigen exposure is reduced. This biological principle has been repeatedly validated in the development of neoantigen-based and mRNA vaccine platforms, which have shown that patients treated before extensive cytotoxic therapy are more likely to mount durable responses. Clinical development has also established feasible endpoints for such strategies. Randomized studies of personal neoantigen vaccines in melanoma and other malignancies have successfully used recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) as primary endpoints, with clinically meaningful benefit observed in the adjuvant setting.^242,274,275 These precedents can be directly applied to IMVs, which share the capacity for durable immunogenicity but have the additional advantage of targeting suppressive elements of the TME.

Practical considerations further strengthen the case for early intervention. Both adjuvant and neoadjuvant settings provide defined treatment windows during which patients are clinically stable and perioperative vaccination can be coordinated with surgery. These intervals allow for priming and boosting of immune responses at a time when effector cell fitness is optimal. Advances in sequencing technologies, epitope prediction algorithms, and scalable vaccine platforms have further increased the feasibility of rapid vaccine design and delivery in these time-sensitive contexts.^242,276 Collectively, these insights provide a strong rationale for extending IMV development into earlier disease stages, where the biological, clinical, and practical conditions are most favorable.

As described above, the phase III melanoma trial of an IDO/PD-L1 peptide vaccine in combination with anti–PD-1 therapy showed that the clinical effect of the combination was especially prominent among PD-1–naïve patients, and the median progression-free survival was extended to 24.8 months compared with 11.0 months in the control arm, a difference that was statistically significant.²²⁵ Building on these findings, the future of IMV–checkpoint combinations is poised to shift toward adjuvant therapy, where patients are uniformly PD-1–naïve and the potential for durable immune control is greatest. Clinical programs have already moved in this direction. A randomized trial is evaluating IO102/IO103 in combination with pembrolizumab in resectable melanoma and squamous cell carcinoma of the head and neck in both neoadjuvant and adjuvant settings (NCT05280314).

Taken together, these results establish a strong foundation for IMVs in the adjuvant setting. By targeting suppressive niches that drive recurrence, combining safely with checkpoint blockade and enabling long-term dosing in clinically stable patients, IMVs provide a biologically and clinically rational strategy to extend disease control beyond resection. Their integration into adjuvant protocols may define the next major advance in therapeutic vaccination.

Neoadjuvant setting

The neoadjuvant setting has emerged as another promising arena for therapeutic cancer vaccines, including IMVs, because it allows treatment to be administered while the primary tumor is still intact and before resection. This intact tumor serves as a reservoir of antigens that can broaden the priming of T-cell repertoires and seed systemic immune memory. Importantly, resection after neoadjuvant vaccination permits direct evaluation of vaccine-induced changes in the TME, including immune cell infiltration, tertiary lymphoid structure formation, and adaptive resistance pathways.

Clinical experience from other vaccine platforms supports this rationale. Neoadjuvant GVAX in pancreatic ductal adenocarcinoma induced tertiary lymphoid aggregates in the majority of tumors, correlating with improved overall survival compared to adjuvant-only vaccination.²⁷⁷ Trials combining GVAX with checkpoint inhibitors and stereotactic body radiotherapy (SBRT) showed that vaccines could enhance CD8⁺ T-cell infiltration and pathologic response rates, although compensatory immunosuppressive mechanisms such as PD-L1 upregulation and myeloid recruitment were also observed.²⁷⁸ Similarly, viral vector vaccines such as talimogene laherparepvec (TVEC) in triple-negative breast cancer demonstrated high pathologic complete response rates when integrated with chemotherapy.²⁷⁹ Neoantigen-based RNA and DNA vaccines in pancreatic cancer and hepatocellular carcinoma have further demonstrated that strong T-cell responses in the perioperative setting correlate with improved recurrence-free survival.^127,275

IMVs fit naturally into this paradigm because of their ability to inflame and desuppress the TME prior to surgery, potentially improving both resection outcomes and systemic disease control. Early clinical results support this rationale. In the phase II HN1901 window-of-opportunity trial, patients with primary squamous cell carcinoma of the head and neck received short-term preoperative vaccination with the IDO1-derived peptide IO102 or the PD-L1-derived peptide IO103.²⁸⁰ The treatment was well tolerated. Two of five patients vaccinated with IO103 exhibited tumor shrinkage, and one showed a positive IFNγ ELISpot response accompanied by high intratumoral CD8⁺ T-cell density and strong PD-L1 and CD274 expression. Spatial transcriptomic analyses revealed increased expression of inflammation-related gene programs in IO103-treated tumors compared with controls, demonstrating the capacity of IMVs to remodel the TME within a short neoadjuvant timeframe.²⁸⁰

Collectively, these findings suggest that neoadjuvant vaccination can not only augment local tumor control but also generate durable systemic immunity, positioning vaccines as a rational partner in perioperative regimens. For IMVs specifically, this strategy is especially compelling: by inflaming and desuppressing the TME before surgery, IMVs may both enhance the quality of resection and reduce the likelihood of recurrence. Nonetheless, challenges remain regarding timing, since neoadjuvant windows before surgery may be too short to elicit optimal immune responses.²⁸¹ Future trials will need to balance these logistical constraints with the immunological advantages of the approach while integrating IMVs with checkpoint inhibitors, radiotherapy, or chemotherapy to maximize efficacy.

Clinical implications across disease stages

In summary, although IMVs were initially developed and validated in patients with advanced malignancies, insights from the broader cancer vaccine field suggest that their greatest impact may be achieved in earlier disease stages. IMVs are particularly well-suited for this transition because they can inflame and remodel the TME prior to resection, sustain an immune-permissive state after surgery, and be administered safely over extended periods of follow-up. The ongoing adjuvant and neoadjuvant trials of IO102/IO103 in melanoma and squamous cell carcinoma of the head and neck parallel the trajectory of mRNA and neoantigen vaccines but have the additional advantage of directly targeting immunoregulatory and stromal biology. The clinical development pathway has therefore moved from proof-of-concept in late-stage disease to testing in perioperative, potentially curative settings. If these trials confirm the preclinical and translational rationale, IMVs will become a transformative component of cancer immunotherapy in the coming years.

Applications in infectious diseases

Many clinically challenging infections, most clearly chronic or relapsing infections, are sustained by the formation of locally immune-suppressive niches that mirror key organizational features of the tumor microenvironment, including dominant checkpoint signaling, metabolic suppression, and regulatory cytokine circuits.^282,283 Importantly, related inhibitory programs can also be rapidly induced during acute infection and may disproportionately blunt protective immunity in older individuals and other high-risk hosts (e.g., patients with cancer and treatment-related immune dysfunction), providing a rationale for extending IMV principles beyond classical chronic infection settings.⁷² The therapeutic principles that underpin IMVs in oncology, therefore, extend naturally into infectious diseases in general.⁷² In both cancer and infection, the host immune system is not defeated solely by the antigenic complexity of the challenge but also by the establishment of regulatory microenvironments that constrain effector activity.^282,283 Pathogens, such as tumors, co-opt immune checkpoints, metabolic enzymes, and regulatory cytokines to create niches in which they can persist. IMVs offer a strategy to dismantle such niches and restore effective immunity by expanding anti-Tregs directed against these host-derived molecules.

Parallels between tumors and infectious niches

Chronic viral infections such as HIV, HBV, and HCV are characterized by persistent antigen exposure and inflammatory environments that paradoxically promote immune suppression.^284–287 Many of the same regulatory cells and molecules that shape the TME are also active in these infectious settings. Dendritic cells and macrophages in infected tissues frequently upregulate IDO, which depletes tryptophan and accumulates kynurenine,²⁸⁸ leading to metabolic starvation of effector T cells and promoting the differentiation of Tregs.²⁸⁹ PD-L1 expression is elevated on hepatocytes, Kupffer cells, and infected antigen-presenting cells, enforcing exhaustion of virus-specific CD8⁺ T cells.²⁹⁰ ARG1 is commonly upregulated in hepatic myeloid cells during HBV and HCV infection, where it contributes to fibrosis and impairs CD8⁺ T-cell proliferation.²⁹¹ TGF-β is abundant in chronically infected livers and in HIV-infected mucosa, where it promotes fibrosis, tolerance, and barrier dysfunction.^292–295

Comparable mechanisms also occur in acute infections. Transient surges of TMAs such as IDO, PD-L1, and TGF-β suppress effector responses at the precise time when viral clearance is most urgently needed.¹⁵⁸ Epithelial-derived TGF-β has been shown to function as a pro-viral factor in the lung during influenza infection,²⁹⁶ and increased IDO activity has been associated with poor outcomes in hospitalized influenza patients.²⁹⁷ In COVID-19, PD-L1–expressing dendritic cells were found to be functionally impaired,²⁹⁸ and severe disease was associated with increased activity of ARG and TGF-β.²⁹⁹ Suppressive pathways involving the same molecules are also evident in parasitic and bacterial infections.³⁰⁰ In Leishmania major, regulatory immune cells inhibit protective T-cell immunity, and during Listeria monocytogenes infection, dendritic cells and macrophages can acquire tolerogenic properties that prevent effective effector priming.³⁰¹

Taken together, these mechanisms create environments that closely resemble the TME. Effector cells are excluded or metabolically restricted, suppressive populations expand, and the immune balance shifts toward tolerance rather than pathogen clearance. The concept of ‘microenvironment antigens’ in infection is therefore directly analogous to TMAs in cancer. These host-derived molecules, co-opted by pathogens, establish suppressive niches and are visible to antigen-specific anti-Tregs.

Evidence that anti-Tregs can boost viral immunity

Although no IMVs have yet been tested in infectious diseases, there are strong reasons to expect efficacy. Anti-Tregs have repeatedly been shown to increase T-cell immunity toward viral antigens.³⁴ In vitro experiments demonstrated that PD-L1–specific T cells enhanced the proliferation of influenza- and Epstein‒Barr virus (EBV)-specific T cells in peripheral blood mononuclear cell cultures. Similarly, IDO-specific T cells augmented EBV-specific responses by reacting to IDO⁺ cells and reducing resident Tregs, thereby amplifying antiviral activity. This principle has also been observed in murine tumor models, where IMVs directed against IDO modulated suppressive microenvironments and boosted proinflammatory immunity toward unrelated tumor antigens.²¹²

These findings indicate that the activation of anti-Tregs can enhance antiviral immunity through the simultaneous targeting of dysregulated pathways that are frequently co-opted in infection. By removing or reprogramming microenvironment antigen-expressing regulatory cells, anti-Tregs restore antigen presentation, improve cytokine balance, and create conditions permissive for effector expansion.

Clinical opportunities in chronic and acute infections

The adaptive immune response is an obvious therapeutic target in infectious disease,²⁸⁴ and IMVs represent a rational strategy for both chronic and acute infections. In HIV, IMVs directed against IDO and PD-L1 could reduce T-cell exhaustion and synergize with latency-reversing agents to eliminate viral reservoirs. In HBV, HBV-specific T cells are severely dysfunctional due to persistent inhibitory signaling from regulatory cells.^293,302 Antigen-presenting cells in this context often fail to prime effective responses, instead inducing tolerance marked by PD-L1 and PD-L2 expression and secretion of IDO, ARG, and TGF-β. Importantly, IDO has been shown to directly suppress HBV vaccine responses in hemodialysis patients,^303,304 suggesting that IDO-targeting IMVs could improve prophylactic vaccine efficacy. In HCV, exhausted antiviral responses are partly facilitated by IDO and other regulatory molecules.²⁹³ In HIV, ARG, TGF-β, and IDO expression in dendritic cells and macrophages directly inhibits antiviral T-cell responses.²⁹⁴

Chronic viral hepatitis provides perhaps the clearest parallel to tumors. Persistent antigen stimulation in HBV and HCV drives hepatocytes, Kupffer cells, and myeloid cells to produce TGF-β, leading to fibrosis, extracellular matrix deposition, and cirrhosis progression. Preclinical data demonstrate that TGF-β–specific T cells can reduce fibrosis, normalize stromal architecture, and improve immunity as well as tissue function.^{49–52,70,163} A similar rationale applies to tuberculosis granulomas, where TGF-β and ARG1 enforce fibrosis and encapsulation; dismantling these barriers with IMVs could accelerate bacillary clearance in conjunction with antibiotics.

In acute infections, IMVs could complement viral vaccines by removing transient regulatory bottlenecks that limit efficacy. In influenza, epithelial-derived TGF-β supports viral persistence in the lung,²⁹⁶ and IDO activity has been linked to poor clinical outcomes.²⁹⁷ In COVID-19, impaired dendritic-cell function and upregulated ARG and TGF-β activity contribute to severe disease.^298,299 These findings suggest that IMVs might strengthen acute antiviral responses, particularly in elderly individuals, who often fail to mount robust immunity to conventional vaccines.

IMVs and immunosenescence

Immunosenescence represents a major challenge for vaccine efficacy in elderly populations. Declines in naïve T and B-cell compartments, impaired dendritic-cell function, and weakened germinal center responses limit adaptive immunity.³⁰⁵ IMVs offer a strategy to overcome this barrier by specifically activating anti-Tregs and reprogramming innate immune cells. Upon activation, anti-Tregs eliminate or reprogram suppressive cells expressing IDO, PD-L1, ARG, or TGF-β, thereby shifting the immune landscape toward a proinflammatory and immunocompetent state.⁵⁵ Importantly, PD-L1- and IDO-specific T cells have been shown to enhance influenza- and EBV-specific T-cell proliferation in vitro, demonstrating that anti-Tregs can directly boost viral immunity. Similarly, dendritic-cell–based vaccines supplemented with PD-L1-derived epitopes significantly enhanced both CD4⁺ and CD8⁺ T-cell responses. Importantly, clinical cancer trials of IMVs targeting IDO and PD-L1 have demonstrated dramatic improvements in adaptive immunity in the phase II melanoma trial in a very old patient population.²²² These data underscore the translational potential of IMVs for infectious disease vaccines in elderly populations.

Future perspectives

Although the first clinical trial of IMVs in infectious diseases has not yet been initiated, evidence from immuno-oncology has firmly established their rationale. Antigen discovery and functional assays have identified IDO, PD-L1, ARG1/2, and TGF-β as valid targets for anti-Tregs. Preclinical studies have demonstrated that activation of anti-Tregs can modulate immune suppression and amplify antiviral immunity in vitro, while vaccination against these targets in cancer models remodels suppressive niches and enhances effector T-cell responses.²¹² The next step is the initiation of early-phase trials in chronic viral infections such as HBV, HCV, and HIV, with further extension to tuberculosis and selected acute viral infections. In this regard, IMVs could be applied in tuberculosis by targeting PD-L1 and IDO in TB lesions, thereby weakening local regulatory networks and enhancing anti-mycobacterial immunity while avoiding the systemic overactivation associated with broad checkpoint blockade.³⁰⁶ Clinical trials have documented that IMVs can be administered safely over long periods without inducing systemic autoimmunity.²²² This lowers the barrier to translation compared with entirely novel vaccine platforms. From a longer perspective, IMVs may follow the trajectory already seen in oncology, moving from advanced disease into adjuvant and neoadjuvant settings. In infections, this would translate into both therapeutic vaccination and potential prophylactic or adjunctive use.

A particularly compelling opportunity lies in elderly populations, where immunosenescence severely limits the efficacy of conventional vaccines. IMVs could substantially improve prophylactic and therapeutic vaccine responses in elderly individuals, who remain disproportionately vulnerable to both acute and chronic infections.

By targeting the shared regulatory ecosystems that pathogens and tumors exploit, IMVs represent a unifying immunotherapeutic concept with the potential to transform treatment across oncology and infectious diseases while simultaneously addressing the critical unmet need to restore vaccine responsiveness in aging populations.

Applications in autoimmune diseases

Autoimmune disorders arise when the equilibrium between effector and regulatory arms is perturbed toward exuberant inflammation.^307–309 Under physiological conditions, this same equilibrium is maintained by reciprocal networks in which regulatory cells are themselves policed by antigen-specific effector mechanisms.²

Risks of excessive anti-Treg activity

As described in detail in this review, spontaneous T-cell responses to immunoregulatory proteins have been documented in humans across health and disease.^310,311 Since these responses are not confined to cancer cohorts but are also present in healthy donors without any sign of autoimmunity, it is suggested that tolerance to these self-antigens is permissive rather than absolute and may serve a physiological role in keeping suppression context dependent.⁵⁵

FoxP3-specific cytotoxic T cells have been mapped with HLA-A2 tetramers expanded from peripheral blood.^54,172 These T cells release IFN-γ, TNF-α, and granzyme B and can lyse FoxP3⁺ malignant T-cell lines. Dendritic-cell vaccines encoding FoxP3 mRNA induced strong cytotoxic T-cell responses, depleted FoxP3⁺ Tregs within tumors, and enhanced protection when administered together with tumor-antigen vaccines.¹⁷³ While these findings highlight opportunities, they also underscore caution. Targeting FoxP3⁺ cells indiscriminately could provoke or exacerbate autoimmune phenomena if peripheral Treg pools are broadly reduced. Indeed, in an atherosclerosis model, vaccination with FoxP3-transfected dendritic cells reduced Tregs systemically and worsened disease,¹⁷⁴ reminding us that physiologic Treg function is protective in many autoimmune-prone tissues. One potential mechanistic contributor to autoimmune flares could be excessive activation of anti-Treg responses, leading to local depletion of Tregs within inflamed tissues, thereby lowering the threshold for self-directed immune activity. Although no autoimmune reactions have been observed in IMV clinical trials thus far, careful evaluation will be essential, as the concept is explored in autoimmune indications where immune regulation is already compromised. Theoretical risk may increase with multiantigen IMV constructs that include lineage-defining regulatory targets (e.g., FoxP3) in tissues where regulatory circuits are required to maintain local tolerance. At present, the circulating frequencies of anti-Tregs in rheumatologic and autoimmune diseases are essentially unexplored, and there are no systematic data linking these populations to disease activity or severity. This represents an important knowledge gap in the field that warrants future investigation.

IMVs as normalizers of pathologic suppression

In contrast to their protective role in many settings, regulatory circuits can become pathologically dominant in certain autoimmune diseases, where they impair tissue repair and resolution.³¹² Chronic autoimmune hepatitis complicated by fibrosis and rheumatoid arthritis associated with acquired stromal barriers illustrates how regulatory mechanisms can overshoot and create maladaptive microenvironments. In these contexts, IMVs offer the potential to act as microenvironment sculptors, designed not to abolish regulation but to normalize it. By selectively reducing maladaptive suppression and limiting fibrosis while preserving systemic tolerance, IMVs could restore a more physiological balance. The rationale appears particularly strong in fibrotic autoimmune diseases. TGF-β exemplifies this dual role, functioning both as an immunoregulatory cytokine and as a central driver of fibrosis in systemic sclerosis, idiopathic pulmonary fibrosis, autoimmune hepatitis, and related conditions.^313–315 Vaccination against TGF-β selectively expanded T cells that recognize fibroblasts and stromal cells in inflamed tissues, thereby reducing collagen deposition, reversing myofibroblast activation, and restoring normal tissue architecture. Because IMVs exert their effects only in sites of high antigen density, systemic TGF-β functions such as wound healing and basal tolerance are expected to remain intact, an important consideration given the concern of toxicity that accompanies systemic targeting of TGF-β.^158,314

Principles for safe clinical translation

Any clinical translation of IMVs into autoimmune disease must be guided by rigorous risk management. Candidate vaccines should prioritize antigens and regimens that restrict activity to inflamed niches, for example, epitopes that are presented only under specific cytokine or metabolic conditions. Early trials should integrate detailed immune monitoring of regulatory T-cell numbers and function in both blood and tissue, together with clinical indices, to detect emerging disequilibria before they manifest as disease flares. Such monitoring should include longitudinal assessment of circulating and tissue Treg abundance/function where feasible, autoantibody emergence, and inflammatory biomarkers, with prespecified stopping rules for early signals of organ-specific immune dysregulation. Target selection is equally critical. IDO, PD-L1, ARG1/2, and TGF-β are context-induced regulators that become overexpressed in inflammatory microenvironments. In immune-mediated fibrotic diseases, TGF-β- or ARG2-directed IMVs may therefore represent safer initial test cases than FoxP3-directed approaches, which directly target the lineage-defining transcription factor of Tregs. Human anti-Treg repertoires against microenvironmental antigens are already well documented, and clinical experience from oncology indicates that vaccination preferentially acts where antigen expression is highest.

Summary

The field of IMVs and autoimmunity presents both caution and promise. Indiscriminate disruption of regulatory circuits can exacerbate disease, yet antigen-dependent modulation of regulation, the mechanism exploited by IMVs, enables selective and context-dependent attenuation of suppression that may re-establish immune balance. Human and animal studies confirm that T cells specific for FoxP3, IDO, and PD-L1 exist and are capable of targeting regulatory pathways. Clinical experience in oncology further demonstrates that IMVs can be administered safely for extended periods without inducing systemic autoimmunity. These findings support a cautious and stepwise exploration of IMVs in autoimmune disease, with an emphasis on restoring physiological equilibrium rather than eliminating regulation entirely.

Overall conclusions and future perspectives

The identification of anti-Tregs and the recognition that immunosuppressive microenvironments are themselves antigenic have fundamentally reshaped our understanding of immune regulation in disease. Autoreactive T cells have long been viewed exclusively as pathological, yet it is now evident that anti-Tregs constitute a physiological counterregulatory arm of the immune system that limits excessive suppression. This insight directly led to the development of IMVs, which are designed to expand naturally occurring T-cell repertoires targeting TMAs such as IDO, PD-L1, ARG1/2, and TGF-β, thereby dismantling the cellular and molecular barriers that sustain immune evasion. A defining feature of IMVs is their mechanistic distinction from existing immunotherapies. Whereas immune checkpoint inhibitors release inhibitory signals on preexisting effector T cells and small-molecule inhibitors transiently block individual suppressive pathways, IMVs act upstream by eliminating or reprogramming entire suppressive cell populations. CD8⁺ anti-Tregs mediate direct cytotoxicity against regulatory immune cells, while CD4⁺ anti-Tregs secrete proinflammatory cytokines that re-educate myeloid, stromal, and endothelial compartments. This dual cytolytic and modulatory mechanism enables IMVs to reshape the tumor microenvironment in a context-dependent manner, preferentially targeting sites of high antigen expression while sparing normal tissues, thereby distinguishing IMVs conceptually and functionally from antibody- or inhibitor-based approaches.

Preclinical studies have consistently validated this principle. IMVs targeting IDO, PD-L1, ARG1/2, and TGF-β reduce myeloid suppression, remodel fibrotic stroma, normalize aberrant vasculature, and inflame otherwise immune-excluded tumors. These effects provide a mechanistic explanation for the strong synergy observed between IMVs and checkpoint blockade, tumor-antigen vaccines, and radiotherapy. Importantly, IMVs do not merely augment effector immunity but remove regulatory bottlenecks that constrain the effectiveness of other therapeutic modalities.

Clinical translation has progressed with unusual speed for a vaccine-based strategy. First-in-human studies demonstrated that IMVs can be administered repeatedly over prolonged periods without inducing systemic autoimmunity, confirming the physiological tolerability of expanding self-reactive anti-Tregs. Subsequent phase I and II trials documented immunogenicity, remodeling of suppressive cell populations, and durable clinical benefit in selected settings. The phase III trial of IO102/IO103 combined with anti–PD-1 therapy in advanced melanoma provided the first evidence that therapeutic cancer vaccination can improve progression-free survival in metastatic disease, with a particularly strong benefit in PD-1–naïve and PD-L1–negative patients.

At the same time, the accumulated clinical data also highlight important areas for improvement and potential failure risks. IMV efficacy appears to be highly context dependent, with diminished benefit in heavily pretreated patients and in environments where profound T-cell dysfunction has already developed. This underscores the importance of treatment sequencing, antigen selection tailored to dominant suppressive mechanisms, and strategies to enhance vaccine-induced immune potency. Rational combinations, optimized adjuvant systems, multiantigen formulations, and earlier clinical intervention represent key avenues to overcome these limitations.

Beyond oncology, the implications of IMVs extend into infectious and inflammatory diseases. Chronic infections such as HIV, hepatitis viruses, and tuberculosis generate suppressive microenvironments characterized by the same TMAs observed in tumors. Experimental activation of anti-Tregs has demonstrated the capacity to dismantle suppression and enhance viral immunity. In autoimmunity, the same biology represents both opportunity and risk, emphasizing the need for carefully calibrated approaches that normalize immune suppression without breaking tolerance. Together, these observations support the broader concept of “microenvironment antigens” as unifying therapeutic targets across diverse disease classes.

The expanding diversity of vaccine platforms further strengthens the translational potential of IMVs. Peptide-based vaccines remain the most clinically advanced, with a strong safety record and proven immunogenicity. RNA platforms allow rapid, flexible encoding of multiple TMAs and are entering clinical testing, while DNA-based approaches offer scalable and cost-efficient options validated in other cancer indications. This platform's versatility enables IMVs to be adapted across disease stages, from prolonged adjuvant therapy to rapidly deployable formulations.

Taken together, IMVs represent not merely an incremental advance in cancer vaccination but a new category of immunotherapy defined by its capacity to dismantle regulatory networks that block immunity. Their favorable safety profile, mechanistic breadth, and emerging clinical efficacy position IMVs as transformative agents that complement checkpoint inhibitors, adoptive cell therapies, tumor-antigen vaccines, and conventional oncologic treatments. The field has progressed from the discovery of anti-Tregs to preclinical validation to late-stage clinical benefit in metastatic disease and is now advancing toward curative-intent settings and broader disease applications.

A final conceptual conclusion of this review is that anti-Tregs themselves operate within the same regulatory networks they help counteract and are subject to inhibition by the suppressive populations they target. This observation is conceptually aligned with the immune network theory proposed by Niels Jerne in the early 1970s, which postulated that immune regulation emerges from layered interactions among lymphocytes even in the absence of foreign antigens. Within this framework, anti-Tregs can be viewed as integral components of a broader regulatory system in which suppressive and counterregulatory populations reciprocally influence one another. Although aspects of Jerne’s original model were oversimplified, accumulating evidence supports the view that self-reactive effector and suppressor T cells coexist as part of a tightly regulated immune network that maintains immune homeostasis without inducing pathology. Anti-Tregs, therefore, represent not a breakdown of tolerance but an additional regulatory layer contributing to immune balance.

Acknowledgements

The current study was supported by the National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Denmark. The author wishes to express his sincere gratitude to all current and former members of the MHA group at the National Center for Cancer Immune Therapy, Denmark, whose contributions were essential to the development of the Immune-Modulatory Vaccine concept. The author also extends his heartfelt thanks to friends and collaborators, both national and international, whose dedication, creativity, and support have shaped my work, including esteemed colleagues at IO Biotech. Finally, I would like to thank Charlotte Hald Andersen for her support and help with the refinement of the figures.

Data availability

This is a review article without primary datasets.

Competing interests

M.H.A. is named an inventor on various patent applications relating to the therapeutic use of TMAs for vaccination. The rights of the patent applications have been transferred to Copenhagen University Hospital, Herlev, according to the Danish Law of Public Inventions at Public Research Institutions. The capital region has transferred these patents to the company IO Biotech, whose purpose is to develop immune-modulatory vaccines for cancer treatment.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

This is a review article without primary datasets.

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PERMALINK

Immune modulatory vaccines targeting tumor microenvironment antigens: recent advances in oncology and beyond

Mads Hald Andersen

Abstract

Introduction

Fig. 1.

Fig. 2.

Fig. 3.

Anti-regulatory T cells: discovery and mechanistic framework

Intrinsic IDO- and PD-L1-specific immunity

Expansion of anti-Tregs during inflammation

Anti-regulatory cells as counterparts to regulatory cells

Conceptual implications

Tumor microenvironment antigens (TMAs)

Traditional tumor antigens

Metabolic enzymes

Immune checkpoint molecules

Immunosuppressive cytokines and chemokines

Transcription factors

Lectins

Traditional tumor-associated antigens with stromal expression

Conceptual and translational prioritization of TMAs

Table 1.

Mechanisms of action of anti-Tregs

CD8⁺ anti-Tregs as cytotoxic effectors

CD4⁺ anti-Tregs as cytokine producers and reprogrammers

Dual mechanisms and bystander effects

Fig. 4.

Modulation of specific suppressive cell populations

Fig. 5.

Remodeling of the TME

Potential resistance and escape mechanisms

Preclinical development of immune-modulatory vaccines

IDO and PD-L1 vaccination in preclinical models

Arginase vaccination and myeloid reprogramming

TGF-β vaccination

Additional preclinical IMV models

Principles emerging from preclinical studies

Clinical development of immune-modulatory vaccines

First-in-human studies: IDO vaccination

PD-L1 and PD-L2 vaccination

Combination of IDO/PD-L1 vaccines with PD-1 blockade

Arginase vaccination

TGF-β vaccination

Survivin and VEGF/VEGFR vaccines

Safety and tolerability of immune-modulatory vaccines across clinical settings

IMV vaccine platforms

Clinical summary

Combination strategies

Fig. 6.

IMVs with checkpoint inhibitors

IMVs with tumor-antigen vaccines

IMVs with cellular therapies

IMVs with chemotherapy and radiotherapy

Fig. 7.

Summary of combination rationale

Expanding clinical applications into earlier disease stages

Adjuvant setting

Neoadjuvant setting

Clinical implications across disease stages

Applications in infectious diseases

Parallels between tumors and infectious niches

Evidence that anti-Tregs can boost viral immunity

Clinical opportunities in chronic and acute infections

IMVs and immunosenescence

Future perspectives

Applications in autoimmune diseases

Risks of excessive anti-Treg activity

IMVs as normalizers of pathologic suppression

Principles for safe clinical translation

Summary

Overall conclusions and future perspectives

Acknowledgements

Data availability

Competing interests

Footnotes

References

Associated Data

Data Availability Statement

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