Reprogramming the tumor microenvironment through vaccine strategies to improve clinical outcomes and guide future innovations

Abstract

The tumor microenvironment (TME) is a dynamic, multilayered ecosystem composed of immune cells, stromal elements, vascular structures, extracellular matrix components, and soluble mediators that collectively shape tumor progression, immune evasion, and therapeutic resistance. Vaccines targeting the TME represent an emerging paradigm in cancer immunotherapy, aiming not only to elicit antigen-specific T-cell responses but also to remodel immunosuppressive niches that characterize immune-desert and immune-excluded tumors. By directing immune activation toward non-malignant but functionally critical components—including cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and angiogenic pathways such as VEGF signaling—TME-targeted vaccines seek to convert “cold” tumors into immunologically responsive states amenable to combination treatment. This narrative review synthesizes major advances from 2023 to 2025 in antigen selection strategies, vaccine delivery platforms, clinical developments, and mechanistic insights underlying TME reprogramming. Key challenges, including stromal heterogeneity, cytokine-driven immunosuppressive rebound, and delivery inefficiencies, are examined alongside safety considerations and translational barriers. Future directions—such as integration with immune checkpoint inhibitors, targeting immunometabolic checkpoints like CD39, leveraging macrophage reprogramming approaches, and implementing AI-guided vaccine personalization—are discussed to highlight opportunities for durable tumor control. By consolidating current evidence and outlining emerging innovations, this review aims to support ongoing efforts to advance next-generation TME-directed immunotherapies within the framework of precision oncology.

Introduction

Cancer is not a solitary entity but a complex, evolving system sustained by the tumor microenvironment (TME), a heterogeneous network of malignant cells, immune cell subsets, stromal elements, vascular structures, and soluble mediators that collectively drive tumor growth, metastasis, and immune evasion [1]. Within this environment, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) interact with aberrant vasculature and immunosuppressive signaling pathways—most notably transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1)—thereby establishing a coordinated barrier to effective antitumor immunity [2].

Recent advances in transcriptomic and spatial profiling have refined our understanding of TAM biology, revealing a spectrum of phenotypic and functional states that extend beyond the classical M1/M2 dichotomy [3, 4]. These macrophage subsets differ in metabolic programming, cytokine responsiveness, and spatial localization within the TME, collectively contributing to immune suppression and therapeutic resistance. Such heterogeneity provides a compelling rationale for vaccine strategies aimed at reprogramming or selectively targeting suppressive macrophage populations.

The immunosuppressive architecture of the TME underlies the emergence of so-called “cold” tumors, which are commonly subdivided into immune-desert and immune-excluded phenotypes [5]. Immune-desert tumors are characterized by defective T-cell priming, often due to impaired antigen presentation, whereas immune-excluded tumors generate tumor-reactive T cells that remain spatially confined to the tumor periphery as a result of stromal and vascular barriers [6]. Both phenotypes demonstrate limited responsiveness to immune checkpoint inhibitors such as pembrolizumab and nivolumab, highlighting the need for therapeutic approaches capable of restructuring the TME itself [2, 5].

Traditional cancer vaccines targeting tumor-associated antigens (TAAs) or tumor-derived neoantigens have frequently produced modest clinical benefit, in part because TME-mediated suppression restricts effector T-cell function, limits intratumoral infiltration, and facilitates adaptive resistance [7]. In contrast, emerging TME-targeted vaccines seek to direct immune responses against non-malignant yet functionally essential components of the tumor niche, including CAFs, Tregs, TAM subsets, and angiogenic mediators such as vascular endothelial growth factor (VEGF) [8]. By disrupting stromal barriers and immunosuppressive signaling networks, these strategies aim to convert immunologically cold tumors into immune-responsive (“hot”) lesions and thereby enhance synergy with immune checkpoint blockade and other immunotherapies [9].

Between 2023 and 2025, progress in antigen discovery, mRNA and lipid nanoparticle (LNP) technologies, personalized neoantigen prediction, and rational combination strategies has accelerated clinical translation. Early-phase trials have reported encouraging immunogenicity and preliminary signals of clinical activity in malignancies such as melanoma, pancreatic ductal adenocarcinoma, and glioma [10]. Despite these advances, significant obstacles remain, including stromal and antigenic heterogeneity, cytokine-driven immunosuppressive rebound, delivery inefficiencies, and the logistical and economic challenges associated with individualized vaccine manufacturing [11].

This review synthesizes contemporary developments in TME-targeted vaccine design, clinical progress, mechanistic insights, and emerging innovations. Table 1; Fig. 1 summarize key TME components and their immunosuppressive roles. As a narrative review, this work selectively integrates influential studies and representative clinical evidence to outline evolving therapeutic opportunities rather than providing a systematic synthesis.

Table 1.

Key TME components and their immunosuppressive roles

Component	Role in TME	Immunosuppressive mechanisms	Relevant vaccine targets
Regulatory T cells (Tregs)	Suppress effector T-cell activation	Secretion of TGF-β and IL-10; CTLA-4–mediated inhibition	FOXP3; Treg-associated epitopes [12]
Myeloid-derived suppressor cells (MDSCs)	Impair T-cell proliferation and function	ROS, arginase-1, and IL-10 production; promotion of Treg expansion	S100A9; MDSC subset markers [13]
Cancer-associated fibroblasts (CAFs)	ECM deposition; stromal remodeling; support of tumor vasculature	Secretion of VEGF and FGF; dense ECM limits immune infiltration	FAP; α-SMA [17]
Tumor-associated macrophages (TAMs)	Promote angiogenesis; suppress effector T-cell responses	IL-10, VEGF, and metabolic reprogramming; suppressive TAM subsets	TAM subset antigens; macrophage reprogramming targets [14–16]
Aberrant vasculature	Creates hypoxia; restricts lymphocyte infiltration	VEGF-driven angiogenesis; HIF-1α stabilization	VEGF; VEGFR-directed strategies [18]

Fig. 1.

Key immunosuppressive components of the tumor microenvironment (TME) and their relevance to vaccine targeting. Schematic representation of major cellular and stromal elements contributing to immune suppression within the tumor microenvironment. Regulatory T cells (Tregs), characterized by FOXP3 expression, suppress effector T-cell function through secretion of transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) and through CTLA-4–mediated inhibitory signaling [12]. Myeloid-derived suppressor cells (MDSCs) inhibit T-cell activity via production of reactive oxygen species (ROS) and arginase-1 [13]. Tumor-associated macrophages (TAMs) comprise heterogeneous suppressive subsets that promote angiogenesis and immune evasion through VEGF and immunoregulatory cytokines [14–16]. Cancer-associated fibroblasts (CAFs), marked by fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA), contribute to extracellular matrix (ECM) deposition and physical exclusion of immune cells [17]. Aberrant, VEGF-driven tumor vasculature induces hypoxia and restricts lymphocyte infiltration [18]. Solid arrows indicate established immunosuppressive mechanisms, while dashed arrows denote indirect or context-dependent interactions. Red stars highlight representative targets for TME-directed vaccine strategies

Methods

This article is a narrative review summarizing advances in tumor microenvironment (TME)–targeted cancer vaccines published from 2023 to 2025. Narrative reviews do not employ predefined protocols, structured study selection, or formal risk-of-bias assessments; therefore, no registration was performed. Evidence included in this review derives from influential peer-reviewed publications, representative preclinical studies, and clinical trial reports, including trials indexed in publicly available registries such as ClinicalTrials.gov. The goal of this review is to synthesize mechanistic insights, translational developments, and emerging therapeutic strategies rather than provide an exhaustive or systematically filtered evidence base.

The tumor microenvironment: composition and immunosuppressive mechanisms

The TME is a dynamic and highly coordinated ecosystem that actively supports tumor growth, immune evasion, and therapeutic resistance. Its cellular components include several immunosuppressive populations with specialized functions. Regulatory T cells (Tregs), defined by FOXP3 expression, suppress antitumor immunity through secretion of transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), and by engagement of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), which inhibits costimulatory signaling required for T-cell activation [12].

Myeloid-derived suppressor cells (MDSCs) impair T-cell proliferation via reactive oxygen species (ROS), arginase-1, and IL-10, while simultaneously promoting Treg expansion [13].

Tumor-associated macrophages (TAMs)—particularly M2-polarized subsets characterized by markers such as CD163—produce vascular endothelial growth factor (VEGF), IL-10, and matrix-remodeling enzymes that promote angiogenesis, suppress effector T-cell responses, and support tumor invasion [14].

Recent transcriptomic analyses demonstrate that TAMs comprise multiple functional subsets extending beyond the M1/M2 model, with distinct metabolic, cytokine-responsive, and spatial phenotypes that contribute variably to immunosuppression and therapeutic resistance [15, 16].

Cancer-associated fibroblasts (CAFs), marked by fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA), produce dense extracellular matrix (ECM) that physically impedes T-cell infiltration and modulate immune activity through secretion of VEGF, fibroblast growth factor (FGF), and other stromal mediators [17].

Dysregulated angiogenesis further enforces immune dysfunction. Tumor vasculature, driven by VEGF and other angiogenic factors, is abnormal and leaky, generating hypoxia that stabilizes hypoxia-inducible factor-1α (HIF-1α), promotes PD-L1 expression, and restricts cytotoxic lymphocyte trafficking [18]. Soluble mediators—including PD-L1 and chemokines such as CCL22—reinforce immune escape by inducing T-cell anergy and recruiting additional Tregs [19]. Collectively, these mechanisms establish a multilayered barrier to immune effector function, limiting the efficacy of conventional immunotherapies [20]. A summary of key TME components and their immunosuppressive properties is presented in Table 1.

TME-targeted vaccines attempt to dismantle this immunosuppressive architecture by eliciting immune responses against stromal, vascular, or immunomodulatory elements. For example, vaccines directed at FAP-expressing CAFs have been shown to reduce ECM density and improve immune infiltration in preclinical models, while VEGF-directed vaccines disrupt aberrant angiogenesis and starve tumors of vascular support [21]. Figure 1 illustrates major TME components and their relevance to vaccine design.

Current strategies in TME-targeted vaccines

Tumor microenvironment (TME)–targeted vaccines rely on rational antigen selection and optimized delivery platforms to induce immune responses against non-malignant yet functionally critical components of the tumor ecosystem. By directing immune activation toward stromal, vascular, or immunosuppressive elements, these strategies aim to overcome immune exclusion, enhance intratumoral lymphocyte infiltration, and improve the efficacy of combination immunotherapies.

Antigen selection strategies

Antigen selection is a central determinant of efficacy in TME-targeted vaccination and requires careful balancing among specificity, immunogenicity, and biological relevance. Tumor-associated antigens (TAAs) that are overexpressed within the TME—such as fibroblast activation protein (FAP) on cancer-associated fibroblasts (CAFs) or programmed death-ligand 1 (PD-L1) on tumor and stromal cells—are attractive targets because of their limited expression in normal tissues and their functional contribution to immune suppression [18]. Preclinical studies have demonstrated that FAP-directed vaccination can reduce stromal density and enhance immune cell infiltration by promoting cytotoxic T-cell–mediated elimination of CAFs [19].

In addition to shared TAAs, neoantigens derived from somatic mutations offer a personalized approach to vaccine design. Although most neoantigen vaccines focus on tumor-cell mutations, accumulating evidence indicates that targeting tumor-specific neoantigens can indirectly reshape the immunosuppressive TME by enhancing effector T-cell infiltration and altering stromal–immune interactions. Personalized mRNA neoantigen vaccines, including autogene cevumeran, have demonstrated robust induction of neoantigen-specific CD8⁺ T-cell responses in pancreatic ductal adenocarcinoma and melanoma, supporting the feasibility of individualized antigen selection strategies that modulate the TME without overstating direct stromal mutation targeting [20].

Shared TME antigens involved in angiogenesis and immunometabolic regulation provide additional opportunities for broadly applicable vaccine strategies. Vascular endothelial growth factor (VEGF) is a key regulator of aberrant tumor angiogenesis, and its inhibition has been shown to improve immune cell trafficking and therapeutic responsiveness [21]. More recently, immunometabolic checkpoints such as CD39—an ectonucleotidase expressed by regulatory immune cells and stromal populations—have emerged as promising targets due to their role in adenosine-mediated immune suppression [22, 23]. Multi-antigen vaccine strategies are increasingly explored to address spatial and temporal variability within the TME, with combinatorial targeting of stromal and vascular components proposed to limit immune escape [24].

Antigen expression within the TME is dynamic and shaped by therapeutic pressure, necessitating adaptive monitoring strategies such as serial biopsies or circulating biomarkers. Computational approaches, including machine-learning–assisted epitope prediction algorithms, are increasingly integrated into antigen prioritization pipelines to improve immunogenicity prediction and reduce the risk of antigen loss–mediated resistance [25].

Vaccine delivery platforms

Efficient delivery platforms are essential to ensure antigen uptake by professional antigen-presenting cells (APCs) and to promote effective CD4⁺ and CD8⁺ T-cell priming. mRNA vaccines have emerged as a leading platform due to their rapid manufacturing, scalability, and capacity to encode multiple antigens or immunomodulatory molecules. In addition to antigen expression, mRNA constructs can incorporate immune-stimulatory signals such as OX40 ligand (OX40L) or granulocyte–macrophage colony-stimulating factor (GM-CSF), thereby enhancing APC activation and promoting pro-inflammatory remodeling of the TME [26].

Dendritic cell (DC)–based vaccines involve ex vivo loading of autologous DCs with tumor- or TME-derived antigens prior to reinfusion. DCVax-L, evaluated in glioblastoma, has been associated with prolonged survival and increased intratumoral immune infiltration in late-phase clinical studies, highlighting the translational potential of cell-based platforms despite their logistical complexity [27].

Oncolytic virus–based vaccines, such as talimogene laherparepvec (T-VEC), exert dual antitumor effects by directly lysing tumor cells and inducing localized inflammation through the release of tumor antigens and damage-associated molecular patterns. T-VEC has demonstrated clinical benefit in melanoma and is frequently combined with immune checkpoint inhibitors to amplify systemic antitumor immunity [28].

Finally, lipid nanoparticle (LNP) delivery systems enhance mRNA stability, protect against enzymatic degradation, and facilitate lymph-node targeting. LNP-based platforms have been successfully employed in therapeutic cancer vaccine trials, including self-amplifying mRNA constructs, and are considered central to next-generation TME-directed vaccine development [29].

A comparative overview of vaccine delivery platforms—including mechanisms of action, advantages, limitations, and representative clinical applications—is provided in Table 2, while Fig. 2 schematically illustrates their interactions with immune cells and the tumor microenvironment.

Table 2.

Comparison of tumor microenvironment–targeted vaccine delivery platforms

Platform	Mechanism of action	Key advantages	Major limitations	Representative applications
mRNA vaccines	Encode tumor- or TME-associated antigens and immunomodulatory molecules	Rapid scalable production; multi-antigen flexibility; strong T-cell induction	Intrinsic mRNA instability; dependence on delivery systems	Personalized neoantigen vaccines (e.g., mRNA-4157) [26]
Dendritic cell vaccines	Ex vivo loading of autologous DCs with tumor/TME antigens	High antigen specificity; potent T-cell priming	Labor-intensive; high manufacturing cost; limited scalability	DCVax-L in glioblastoma [27]
Oncolytic virus-based vaccines	Selective infection and lysis of tumor cells	Local and systemic immune activation; synergy with ICIs	Preexisting antiviral immunity; delivery challenges	Talimogene laherparepvec (T-VEC) in melanoma [28]
Lipid nanoparticle platforms	Protect nucleic acids; facilitate delivery to lymphoid tissues/APCs	Enhanced stability; improved lymph node targeting	Manufacturing complexity; formulation optimization required	LNP-formulated therapeutic mRNA vaccines [29]

Fig. 2.

Mechanistic overview of vaccine delivery platforms used in tumor microenvironment (TME)–targeted immunotherapy. Schematic depiction of representative vaccine delivery platforms currently applied in TME-directed cancer immunotherapy. A mRNA-based vaccines encode tumor- or TME-associated antigens that are translated by antigen-presenting cells, resulting in peptide presentation and subsequent T-cell priming. B Dendritic cell (DC)–based vaccines rely on ex vivo loading of autologous DCs with tumor- or TME-derived antigens followed by reinfusion into the patient. C Oncolytic virus–based vaccines selectively infect tumor cells, leading to immunogenic cell death and the release of tumor antigens and damage-associated molecular patterns (DAMPs) that facilitate local immune activation. D Lipid nanoparticle (LNP) delivery platforms enhance nucleic acid stability and promote preferential targeting of lymphoid tissues, thereby improving antigen delivery to antigen-presenting cells. The mechanisms illustrated are derived from preclinical and early-phase clinical studies and are intended to convey general principles rather than tumor-specific outcomes [26–29]

Recent advancements (2023–2025)

Between 2023 and 2025, cancer vaccines capable of modulating the tumor microenvironment (TME) have advanced through early and intermediate stages of clinical evaluation, driven largely by improvements in personalized neoantigen identification and rational combination strategies with immune checkpoint inhibitors.

In melanoma, the personalized mRNA vaccine mRNA-4157 (V940), administered in combination with pembrolizumab, demonstrated a statistically significant improvement in recurrence-free survival in the randomized phase II KEYNOTE-942 trial (NCT03897881; n = 157). The vaccine encodes up to 34 patient-specific neoantigens identified through tumor sequencing and was associated with enhanced neoantigen-specific CD8⁺ T-cell responses and increased intratumoral immune infiltration compared with pembrolizumab alone [31]. Although the vaccine targets tumor-derived neoantigens rather than stromal mutations directly, post-treatment analyses suggest secondary modulation of the TME, including reductions in immunosuppressive immune cell populations, supporting its classification as a functional TME-modifying strategy.

In pancreatic ductal adenocarcinoma, autogene cevumeran—a personalized mRNA neoantigen vaccine—was evaluated in a phase I, non-randomized trial (NCT03289962; n = 16). Sustained neoantigen-specific CD8⁺ T-cell responses were observed in 8 of 16 patients and correlated with delayed disease recurrence following surgical resection [32]. While the vaccine primarily targets tumor-derived neoantigens, responders exhibited immune remodeling characterized by increased effector T-cell infiltration and reduced myeloid-derived suppressor cell signatures, consistent with indirect reprogramming of the immunosuppressive TME.

Glioblastoma remains particularly challenging due to its profoundly immunosuppressive microenvironment and limited lymphocyte trafficking across the blood–brain barrier. Therapeutic vaccination strategies targeting IDH1-R132H mutations have demonstrated encouraging immunogenicity. In the NOA-16 trial and subsequent extensions, IDH1-targeted peptide vaccines induced mutation-specific CD4⁺ T-cell responses and were associated with prolonged survival compared with historical controls [33]. These effects are attributed to enhanced immune activation rather than direct targeting of stromal neoantigens, underscoring the need for conservative interpretation of TME-specific mechanisms.

Collectively, these trials—summarized in Table 3 and visualized in Fig. 3—illustrate the growing clinical relevance of vaccines capable of reshaping the immune contexture of tumors, even when antigen targets are tumor-specific. However, heterogeneity in trial design, endpoints, and patient populations precludes formal meta-analysis. As of August 2025, more than 100 clinical trials evaluating mRNA-based cancer vaccines were registered across ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, many of which incorporate combination approaches aimed at overcoming TME-mediated resistance [34].

Table 3.

Representative clinical trials of vaccines with tumor microenvironment–modulating effects (2023–2025)

Cancer type	Vaccine	Platform	Combination therapy	Clinical outcome	Trial Identifier / phase	Sample size (n)	Primary endpoint	Key endpoint results	Grade ≥ 3 safety events	Median follow-up	Risk of bias	References
Melanoma	mRNA-4157 (V940)	mRNA	Pembrolizumab	Reduced recurrence risk; neoantigen-specific T-cell responses	NCT03897881 / II	157	Recurrence-free survival (RFS)	HR 0.56 (95% CI 0.36–0.89; p = 0.013); 74.8% vs. 55.6% RFS at 2.5y	Comparable to pembrolizumab; no new signals	2.5 years	Moderate (randomized, open-label)	[31]
Pancreatic ductal adenocarcinoma	Autogene cevumeran	mRNA	None	Sustained neoantigen-specific immune responses in subset	NCT03289962 / I	16	Immunogenicity	CD8⁺ T-cell responses in 8/16 patients; delayed recurrence in responders	No grade ≥ 3 vaccine-related events	18 months	High (small, non-randomized)	[32]
Glioma (IDH1-mutant)	IDH1-R132H vaccine	Peptide	None	Mutation-specific T-cell induction; survival vs. historical controls	NCT02135959 / I/II	60	Immunogenicity / OS	Median OS ~ 22 months; survival benefit vs. historical cohorts	Grade 1–2 local reactions only	N/A	High (historical comparison)	[33]

Fig. 3.

Clinical outcomes reported in representative vaccine trials with tumor microenvironment–modulating effects (2023–2025)

Bar chart summarizing reported survival endpoints and relative T-cell responses from selected clinical trials of cancer vaccines with demonstrated tumor microenvironment–modulating effects. Blue bars indicate reported survival outcomes, including recurrence-free survival (RFS) or overall survival (OS), as specified in the original trial reports. Green bars represent relative T-cell responses, shown as qualitative units derived from immunogenicity data rather than direct quantitative comparison. Data are shown for mRNA-4157 (melanoma), autogene cevumeran (pancreatic ductal adenocarcinoma), and the IDH1-R132H vaccine (glioma). Differences in trial design, endpoints, and patient populations preclude formal meta-analysis; the figure is intended for visual comparison only [31–33].

Challenges in tumor microenvironment–targeted vaccine development

Despite recent advances, tumor microenvironment (TME)–targeted vaccines continue to face substantial biological, technical, and translational barriers that limit their clinical impact and durability of response.

Immunosuppressive TME dynamics

Adaptive resistance within the TME represents a major obstacle to sustained vaccine efficacy. Following vaccine-induced immune activation, tumors may upregulate alternative inhibitory pathways, including lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain–containing protein 3 (TIM-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to progressive functional exhaustion of effector T cells [35]. This phenomenon has been observed across multiple cancer types and immunotherapeutic modalities, underscoring the dynamic and context-dependent nature of immune escape rather than vaccine-specific failure [36].

Tumors with low tumor mutational burden (TMB), such as prostate cancer and low-grade gliomas, present additional challenges due to limited neoantigen availability, constraining both tumor-directed and TME-modulating vaccine strategies [37]. Spatial and temporal heterogeneity further complicates antigen targeting, as immune and stromal compositions may differ substantially between primary tumors and metastatic lesions, resulting in incomplete, heterogeneous, or transient immune responses [38].

Beyond immune checkpoint upregulation, alterations in antigen presentation machinery contribute to immune evasion. Downregulation of major histocompatibility complex (MHC) class I molecules and defects in antigen-processing pathways have been documented following immunotherapeutic pressure, thereby limiting CD8⁺ T-cell recognition despite effective vaccine-induced priming [39]. In parallel, cytokine-driven feedback loops—particularly involving transforming growth factor-β (TGF-β), interleukin-10 (IL-10), and immunosuppressive chemokines—can reinforce suppressive microenvironmental states and promote recruitment of regulatory immune populations [40].

Neutral outcomes and safety considerations

Balanced evaluation of TME-targeted vaccine development requires acknowledgment of neutral or limited clinical outcomes. Several therapeutic cancer vaccines have demonstrated robust immunogenicity without translating into measurable survival benefit, highlighting the frequent disconnect between immune activation and clinical efficacy in highly suppressive tumor microenvironments [41]. These findings often reflect biological constraints—including antigen loss, immune exclusion, and compensatory inhibitory signaling—rather than intrinsic failure of vaccine platforms.

Safety considerations are particularly relevant in combination-based strategies. While vaccine monotherapy is generally well tolerated, regimens combining vaccines with immune checkpoint inhibitors or potent immune adjuvants have been associated with increased rates of immune-related adverse events. Across early-phase combination trials, grade ≥ 3 toxicities—including autoimmune manifestations and systemic inflammatory responses—have been reported in approximately 10–15% of treated patients [42, 43]. These observations underscore the importance of careful dose optimization, sequencing, and patient selection when pursuing aggressive immune modulation.

Delivery and immunogenicity challenges

Efficient antigen delivery to professional antigen-presenting cells remains a critical bottleneck for TME-targeted vaccination. mRNA-based vaccines are inherently unstable and depend on optimized lipid nanoparticle (LNP) formulations to achieve effective lymphoid tissue targeting and intracellular delivery. Suboptimal delivery has been associated with variable immunogenicity, particularly in tumors characterized by extensive desmoplasia, abnormal vasculature, or impaired lymphatic drainage [44].

Viral vector–based platforms face additional limitations related to preexisting or rapidly induced anti-vector immunity, which can attenuate antigen expression following repeated dosing and limit sustained immune priming [45]. Intratumoral delivery approaches, while conceptually attractive for localized TME modulation, are invasive and poorly suited for disseminated or metastatic disease, restricting their broader clinical applicability [46].

Adjuvants such as Toll-like receptor agonists or stimulator of interferon genes (STING) activators are often required to enhance vaccine potency but carry inherent risks of excessive inflammation and autoimmunity. Careful formulation, dose selection, and scheduling are therefore essential to balance immunogenicity with tolerability [47].

Clinical and translational barriers

Interpatient variability remains a major impediment to clinical translation. A substantial proportion of patients with solid tumors fail to mount durable immune responses because of baseline immune exclusion, stromal dominance, or profound myeloid-mediated suppression within the TME [48]. Although personalized neoantigen vaccines have demonstrated encouraging immunogenicity, their widespread implementation is constrained by logistical complexity, prolonged manufacturing timelines, and high production costs [49].

Combination regimens integrating vaccines with immune checkpoint inhibitors, cytokines, or other immunomodulatory agents further increase treatment complexity and toxicity risk, complicating dose optimization, trial design, and regulatory evaluation [50]. Moreover, ethical and practical limitations surrounding repeated tumor biopsies restrict comprehensive longitudinal assessment of TME remodeling, limiting mechanistic insight into resistance, relapse, and treatment failure [51].

Future Directions

To address the biological and translational barriers outlined above, multiple complementary strategies are being explored to enhance the effectiveness, durability, and feasibility of tumor microenvironment (TME)–targeted vaccines [52].

Combination approaches integrating vaccines with immune checkpoint inhibitors (ICIs) remain a central focus [53]. By simultaneously enhancing antigen-specific T-cell priming and alleviating inhibitory signaling, such combinations aim to counteract adaptive resistance mechanisms within the TME [54]. Early-phase clinical studies combining oncolytic viruses with ICIs have demonstrated encouraging immune activation and durable responses in melanoma, supporting the concept of TME-inflaming platforms as functional vaccine adjuvants rather than standalone therapies [55]. Nevertheless, careful toxicity monitoring remains essential, as combinatorial immune activation increases the risk of immune-related adverse events.

Beyond vaccine-based strategies, adoptive cell therapies targeting stromal components are being explored as complementary approaches. Chimeric antigen receptor (CAR)–T cells directed against fibroblast activation protein (FAP) have demonstrated stromal depletion and enhanced immune infiltration in preclinical tumor models [56]. While these findings underscore the feasibility of targeting non-malignant TME elements, clinical translation will require stringent safety controls to mitigate on-target, off-tumor toxicity and preserve normal tissue integrity.

Artificial intelligence (AI)–driven personalization is increasingly influencing vaccine design and antigen prioritization. Machine learning frameworks integrating tumor sequencing data with structural prediction and immunopeptidomics have improved epitope selection by enhancing predictions of immunogenicity and major histocompatibility complex (MHC) binding affinity [57]. Although such approaches have shown promise in preclinical cancer vaccine development, successful clinical translation will depend on standardized analytical pipelines, regulatory acceptance, and reproducibility across diverse patient populations.

Emerging nucleic acid platforms may further expand the therapeutic landscape. Circular RNA (circRNA) vaccines offer theoretical advantages over linear mRNA, including enhanced molecular stability and prolonged antigen expression, and have demonstrated immunogenicity in early preclinical cancer models [58]. Similarly, exosome-based delivery systems are under investigation for their potential to enhance lymphoid tissue targeting while reducing systemic toxicity [59]. These technologies remain at an early developmental stage, and their scalability, manufacturing consistency, and regulatory pathways require further clarification.

Early-intervention strategies represent another promising direction. Adjuvant vaccination following surgical resection may target residual disease and prevent re-establishment of an immunosuppressive TME, thereby extending therapeutic windows, particularly in malignancies with high recurrence risk [60]. In parallel, efforts to reduce cost and improve accessibility—including shared neoantigen libraries, modular manufacturing platforms, and harmonized clinical trial designs—will be critical for broader clinical implementation.

Biomarkers and correlative immune analyses

The identification of reliable biomarkers remains essential for patient selection, response monitoring, and mechanistic interpretation. Techniques such as T-cell receptor (TCR) repertoire profiling, spatial transcriptomics, and multiplex immunohistochemistry are increasingly incorporated into vaccine trials to characterize immune remodeling within the TME [61]. Continued analytical and clinical validation of these assays is required before they can be adopted as predictive biomarkers or surrogate clinical endpoints.

Conclusions

Tumor microenvironment–targeted vaccines represent an evolving paradigm in cancer immunotherapy by shifting therapeutic focus from malignant cells alone toward the non-malignant ecosystems that enable immune evasion and treatment resistance. Clinical progress between 2023 and 2025—including personalized mRNA neoantigen vaccines in melanoma and pancreatic ductal adenocarcinoma, as well as mutation-specific vaccination strategies in glioma—demonstrates that vaccine-based approaches can meaningfully influence tumor–immune interactions and, in selected settings, improve clinical outcomes [31–33].

Despite these advances, substantial challenges remain. Adaptive immunosuppressive mechanisms, antigenic and stromal heterogeneity, delivery inefficiencies, and interpatient variability continue to constrain the consistency and durability of clinical benefit. Overcoming these limitations will require integrated therapeutic strategies that combine vaccines with complementary immunomodulatory agents, refined antigen prioritization supported by computational approaches, and rigorously designed, biomarker-driven clinical trials.

With continued methodological refinement, regulatory alignment, and cost-conscious innovation, tumor microenvironment–modulating vaccines may ultimately become an integral component of precision oncology. Their successful implementation could enable durable, patient-specific immune control in malignancies that remain refractory to current therapeutic modalities.

Author contributions

A.M wrote the main manuscript text and prepared figures.

Funding

The author received no specific funding for the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable. This article is a narrative review based exclusively on previously published literature and publicly available data. No new studies involving human participants or animals were conducted by the author.

Consent for publication

Not applicable. The manuscript does not contain any individual-level or identifiable participant data.

Competing interests

The authors declare no competing interests.