Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling

Abstract

IFNs play a critical role in cancer biology, including impacting tumor cell behavior and instructing the tumor microenvironment (TME). IFNs recently have been shown to reprogram tumor metabolism through distinct mechanisms. Furthermore, IFNs shape the TME by modulating immune cell infiltration and function, contributing to the intricate interaction between the tumor and stromal cells. This review summarizes the effects of IFNs on metabolic reprogramming and their impacts on the function of immune cells within the TME, with a particular focus on the dual roles of IFNs in mediating both anti-tumor and pro-tumor immune responses. Understanding the significance of IFNs-mediated processes aids to advise future therapeutic strategies in cancer treatment.

INTRODUCTION OF IFNs

IFNs are key cytokines produced by immune and stromal cells that mediate diverse cellular responses, including immune defense against microbe infection and cancer invasion and progression. They are classified into 3 types: type I IFNs, type II IFNs, and type III IFNs (IFN-Is, IFN-IIs, IFN-IIIs). While IFN-IIIs remain less studied in the tumor microenvironment (TME) and is not the focus to discuss in this review, IFN-Is and IFN-IIs have been extensively characterized and are the focus of this discussion (Fig. 1).

Figure 1. Production of IFNs in the TME and their signaling pathways. Tumor-derived dsDNA, ssRNA, and dsRNA activate intracellular PRRs such as cGAS, IFI16, DAI, RIG-I, and TLR3. This activation triggers STING/TBK1 signaling, leading to the activation of transcription factors IRF3/7 or the NF-κB signaling pathway, driving the expression of IFN-Is. IFN-I or IFN-γ, through engagement with their respective receptors IFNAR1/IFNAR2 or IFNGR1/IFNGR2, stimulates JAK/STAT signaling. Activated JAK proteins phosphorylate STAT1 and STAT2, promoting their dimerization and translocation to the nucleus, where they bind to ISRE or GAS sites to facilitate ISG expression. Additionally, both IFNAR1/IFNAR2 and IFNGR1/IFNGR2 can activate non-STAT pathways, such as the MAPK cascade and mTOR signaling, to induce ISG expression.

cGAS, cyclic GMP-AMP synthase; DAI, DNA-dependent activator of interferon-regulatory factors; RIG-I, retinoic acid-inducible gene I; ISRE, interferon-sensitive response element.

IFN-Is

IFN-Is, the largest subgroup of IFNs, include IFN-α, IFN-β, and several others, such as IFN ε, κ, and ω in humans, as well as δ and τ in other mammals (1,2,3). IFN-Is are produced most predominately by immune cells and stromal cells. The production of IFN-Is is initiated in response to cellular stress signals, particularly in the TME. In malignant cells, leakage of nuclear DNA and other damage-associated molecular patterns (DAMPs) into the cytosol activate pattern recognition receptors (PRRs), such as retinoic acid-inducible gene I, DNA-dependent activator of IFN-regulatory factors, and IFI16 (4,5,6). As a result of these activations, PRRs stimulate IFN-Is production. In immune cells, DAMPs released into the TME interact with endosomal TLRs such as TLR3, further stimulating IFN-Is production (7). Additionally, cytoplasmic tumor DNA can also bind to cyclic GMP-AMP synthase, which activates the Stimulator of Interferon Genes (STING) pathway, leading to robust IFN-Is production (8,9). These cytokines signal through the type I IFN receptor (IFNAR), a ubiquitously expressed receptor composed of the IFNAR1 and IFNAR2 subunits (10,11). Upon binding to IFNAR, IFN-Is activate JAK/STAT pathway as well as other signaling cascades. Upon activation, STAT protein complexes translocate to the nucleus and bind to the promoter regions containing IFN-sensitive response elements, or IFN-γ-activated site (GAS) elements, that drives the transcription of IFN-stimulated genes (ISGs) (12). In addition, IFN-Is also activate the MAPK cascade, particularly the p38 MAPK pathway, and the PI3K/mTOR axis (13,14,15). Through these interconnected mechanisms, IFN-Is orchestrate a broad range of anti-viral, immune-modulatory, and anti-tumor responses, highlighting their pivotal role in both innate and adaptive immunity.

IFN-IIs

IFN-IIs are represented solely by a single member, IFN-γ (15). IFN-γ is primarily produced by NK cells, CD8+ cytotoxic T cells, CD4+ Th1 cells, and certain macrophages and dendritic cell (DC) subsets (16). Its receptor, the type II IFN receptor (IFNGR), is composed of 2 subunits, IFNGR1 and IFNGR2, which are intracellularly associated with JAK1 and JAK2 to mediate downstream signaling (13,15,16). The binding of IFN-γ to IFNGR triggers receptor dimerization, which activates JAK1 and JAK2, leading to the phosphorylation and activation of STAT1 transcription factors. Activated STAT1 homodimers translocate to the nucleus, where they bind GAS elements in ISG promoter regions to initiate transcription (17,18,19). The full transcriptional activity of STAT1 requires interaction with nuclear co-activator proteins, such as p300, cAMP-responsive element-binding protein, and mini-chromosomal maintenance deficient 5, enhancing the expression of a wide range of genes (15). In addition to the JAK/STAT pathway, IFN-γ signaling also activates several non-STAT pathways, including MAPK, PI3K, JNK, CaMKII, and NF-κB, which collectively contribute to its diverse biological effects (20). The regulation of IFN-γ production involves distinct mechanisms in innate and adaptive immunity. In innate immunity, NK and NK T cells are the primary producers; while in adaptive responses, CD8+ and CD4+ T cells serve as major paracrine sources (21). These cells are stimulated by proinflammatory cytokines, such as IL-12, IL-15, IL-18, IL-21, as well as tumor- or pathogen-derived antigens (22,23). Additionally, IFN-γ production is enhanced through an established positive feedback loop where IFN-γ itself amplifies its own secretion (24,25). In inflamed or tumorous tissues, proinflammatory cytokines activate transcription factors such as STAT-4, T-box transcription factor (T-bet), activator protein 1, and Eomesodermin. These elements drive the transcription of IFN-γ, ensuring its sustained production under pathological conditions (18,26,27,28). This tightly regulated system provides the pivotal role of IFN-γ in orchestrating immune responses, particularly within the context of inflammation and tumor immunity.

PARADOXICAL ROLES OF IFNs IN THE TME

The TME is a complex ecosystem crucial for cancer initiation, progression, and immune regulations. It comprises tumor cells, the extracellular matrix, and various noncancerous cells, including immune cells and stromal cells. Poor vascularization, chronic inflammation, and high metabolic activity of tumor cells in the TME create hostile microenvironment, characterized by hypoxia, acidosis, and nutrient deprivation. These conditions impair the function of anti-tumor immune cells, such as CD4+ and CD8+ T cells and DCs, due to limited glucose availability for their own glycolysis and extracellular acidosis (29,30,31,32). This leads to substrate competition and a reduction in anti-tumor activity. In contrast, pro-tumor immune cells, such as intratumoral Tregs, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) adapt well to this environment, continuously suppress the anti-tumor immune responses and are more tolerant of high lactic acid levels in the TME, that can support immune evasion and tumor growth (33,34,35,36,37). In addition to those known metabolic parameters, the presence of IFNs, particularly type I (IFN-I) and type II IFN-γ, has been revealed to shape the TME and coordinate anti-tumor immunity. IFN-γ, a pleiotropic cytokine different from IFN-Is, orchestrates both pro-tumorigenic and anti-tumor responses in the TME. As a critical mediator of innate and adaptive immunity, IFN-γ activates immune responses while preventing excessive inflammation and tissue damage. In the TME, IFN-γ induces apoptosis and senescence in tumor cells (38,39) However, it also promotes immune-suppressive pathways by upregulating immune checkpoint molecules and indoleamine-2,3-dioxygenase (IDO) that can promote tumor immune evasion (40,41,42). This dualistic nature of IFN-γ possesses its paradoxical effects, acting both as a tumor suppressor and a developer of immune evasion (23). While IFNs play a vital role in supporting anti-tumor immunity, their complex roles necessitate careful modulation to optimize therapeutic strategies against cancer progression. Several studies have shown that metabolic reprogramming is essential for functional IFN-Is and IFN-γ responses (43,44). However, the mechanisms underlying this reprogramming remain poorly characterized. This metabolic reprogramming is likely governed by a combination of intrinsic cellular factors and extrinsic signals within the TME (11,43). Importantly, the metabolic stress occurring in the TME can also impair IFNs production from tumor-infiltrating immune cells (Fig. 2) (45,46,47).

Figure 2. The influence of IFNs on tumor metabolic reprogramming and their impact on the immune cells. In the early stages of tumor development, IFNs play a crucial role in immune cell activation, including M1 polarization, DC maturation, CD8+ T cell priming and differentiation, and NK cell activation. At this stage, CD8+ T cells and NK cells exert anti-tumor responses to restrict tumor growth. Simultaneously, IFNs also promote tumor cells to undergo a metabolic shift from OXPHOS to aerobic glycolysis. This metabolic reprogramming drives tumor cells to express PD-L1, IDO, CD47, and produce higher levels of lactate, leading to immune evasion mechanisms such as increased Treg survival, M2 polarization, IDO expression in DCs, CD8+ T cell exhaustion, and inhibition of NK cell function.

THE INTERSECTION OF GLYCOLYSIS AND IFNs

IFN-stimulated fibroblasts, macrophages, and DCs exhibit elevated glycolytic activity, driven by signaling pathways such as PI3K/AKT, which enhances glucose uptake (48). The INFAR engagement and activation of TYK2 are linked to increase glycolysis-mediated lactate production (49). In context of viral infections or in chronic diseases linked to IFN-Is activation, studies have shown that disrupting glycolysis impairs immune responses against respiratory syncytial virus and coxsackievirus, underscoring the importance of this metabolic adaptation (48,50,51). Moreover, plasmacytoid DCs stimulated with IFN-α exhibit increased glycolysis alongside elevated fatty acid (FA) oxidation and oxidative phosphorylation (OXPHOS), driven by mTOR activation, to meet the high energy needs of their immune responses (52). These metabolic shifts have implications for various chronic diseases, including tumors, multiple sclerosis, and systemic lupus erythematosus, where IFN-I-mediated bioenergetic changes contribute to disease pathogenesis (53). Indeed, we recently also revealed that IFN-γ exposure during early stage of immunosurveillance can promote tumor cells to acquire higher c-Myc expression and glycolytic activity via epigenetic reprogramming (54). This finding highlights that IFN-γ can modulate cancer evolution as a result of immunoediting. Importantly, the role of IFN-γ on shaping tumor metabolism as well as metastatic potential is also reported in other studies (55). On the other side, the transition from OXPHOS to aerobic glycolysis is crucial for the activation and effector functions of CD8 T cells (56,57). This metabolic shift, mediated by the mTORC1-HIF-1 pathway, supports the production of biosynthetic precursors and effector molecules, such as IFN-γ, IL-2, IL-17, and granzyme B (30,56,58,59). HIF-1α, a critical regulator of cellular adaptation to hypoxia, is indispensable for glycolysis and IFN-γ production in hypoxic T cells. Stabilization of HIF-1α amplifies glycolytic activity and enhances IFN-γ output, while its deletion or glycolysis inhibition drastically reduces these processes (60,61,62). This indicates the role of glycolysis as a metabolic backbone for IFN-γ production in the hypoxic TME.

THE INTERSECTION OF OTHER METABOLIC PROCESSES AND IFNs

Lipids play a critical role in shaping the TME and modulating immune responses, particularly IFNs production (63). FAs, cholesterol, and prostaglandins disrupt anti-tumor immunity by interfering key processes of antigen presentation and T-cell activation (64). Saturated FAs and prostaglandins suppress IFN-γ production in T cells by impacting T cell metabolic program (65). Additionally, lipid accumulation in MDSCs, driven by FATP2, generates ROS, reducing T-cell proliferation and impairing the ability of T cells to produce IFN-γ and TNF-α (66,67). Cholesterol further impacts IFNs signaling by altering membrane microdomains essential for immune receptor function (68). Overall, targeting lipid metabolism might offers therapeutic potential to restore IFN-Is production and enhance anti-tumor immunity.

Amino acid metabolism also plays a critical role on regulating IFNs production within the TME, contributing to immune suppression and tumor progression (69). IFN-Is responses are intricately linked to amino acid metabolism, particularly through pathways involving arginine and nitric oxide (NO) (70). IFN-Is promote the expression of inducible nitric oxide synthase (iNOS) in macrophages, leading to elevated NO and reactive nitrogen species that have cytotoxic effects against tumors (71). However, the reciprocal regulation caused by arginase (Arg) and iNOS affects the metabolic complexity. For example, iNOS activity inhibits Arg-1 to increase arginine availability for NO production (72). In contrast, chronic IFN-Is signaling in certain contexts, such as viral infections, can upregulate Arg activity, contributing to inflammation-induced immune dysfunction and tumor immune evasion (73). IFN-γ-stimulated DCs upregulate IDO-1, leading to tryptophan depletion and the generation of immunoregulatory kynurenine metabolites (74,75). This action suppresses T cell proliferation and effector function. Similarly, Arg-1, induced by cytokines, such as TGF-β and IL-4, impairs CD8+ T cell proliferation and IFN-γ secretion by depriving arginine availability to CD8+ T cells (76). These findings underscore the intricated intersection between IFNs and amino acid metabolism on orchestrating anti-tumor and immunosuppressive effects, suggesting that modulations for amino acid metabolism could tailor IFNs-driven immune responses in cancer.

EFFECTS OF IFNs ON REMODELING THE TME

Cancer cells

Both IFN-Is and IFN-IIs can act directly on tumor cells, exerting dual pro-tumor or anti-tumor and context-dependent effects (77). IFN-Is directly target malignant cells by inducing apoptosis and cell cycle arrest, often through upregulation of tumor suppressor proteins like p53 (78). These effects inhibit cellular transformation and hematopoietic tumor growth by activating pathways such as SIRT2/CDK9/STAT1 and ULK1 signaling (79,80). IFN-Is also enhance tumor immunogenicity by upregulating NK cell ligands and MHC class I molecules on tumor cell surfaces, making them more vulnerable to immune-mediated killing (81). Moreover, IFN-Is responses are critical for the efficacy of DNA damage-inducing therapies, including chemotherapy and radiation, which rely on IFN-stimulated pathways for eliciting anti-tumor effects (82,83). However, prolonged IFN-I signaling can paradoxically promote tumor survival by upregulating pro-survival ISGs, such as those involved in the IFN-related DNA damage resistance signature (84). Recent study also shows that IFN-Is reprogram tumor cells metabolism toward OXPHOS for ATP production which can combine the inhibitors of CD39 or CD73 with CD47-SIRPa blockade to mount for better tumor control (85). On the other hand, IFN-γ similarly impacts cancer cells by increasing their antigenicity and susceptibility to immune responses (23,40,86). It upregulates MHC class I molecules, enhances antigen presentation, and drives direct tumor cell death via pathways involving p21, p27, and p53 signaling (87,88). IFN-γ also promotes ferroptosis and autophagy-associated apoptosis in cancer cells, particularly by disrupting metabolic pathways such as cystine/glutamate transport (89). Additionally, IFN-γ modifies the TME by reducing suppressive macrophage recruitment through downregulation of CXCL8 expression in tumor cells (90). However, IFN-γ can also enable immune evasion in specific contexts, such as by inducing PD-L1 and other immunosuppressive molecules like CD47 upregulation on tumor cells, which inhibit cytotoxic immune responses (91,92). Sustained IFN-γ signaling may lead to the selection of immune-resistant tumor variants or enhance epithelial-to-mesenchymal transition (EMT), contributing to metastasis and therapy resistance (93). Study by us also revealed that T cell-mediated IFN-γ signaling induces STAT3-dependent c-Myc upregulation in tumor cells, enabling them to shift from OXPHOS to aerobic glycolysis (54). This STAT3-c-Myc-mediated metabolic reprogramming suppresses senescence and synergizes with the STAT1-PD-L1 pathway, thereby facilitating tumor immune evasion (54,94). These findings indicate the complex and dual roles of IFNs in directly influencing tumor cell survival and immune interactions.

T cells

CD4+ T cells, particularly Th1 cells, play a pivotal role in orchestrating anti-tumor immune responses. Both IFN-I and IFN-γ drive CD4+ T cell polarization toward the Th1 phenotype, characterized by high IFN-γ production and IL-12 receptor expression (95). This polarization prevents differentiation into pro-tumor Th2 cells and sustains macrophage and T cell activation. IFN-γ mediates this through STAT1-dependent T-bet activation, creating a positive feedback loop that reinforces the Th1 lineage (13,96). However, sustained IFN-Is exposure, as observed in chronic infections, can reduce CD4+ T cell numbers, potentially impairing their contributions to immune responses in the TME (97). These dual effects point out the context-dependent impact of IFN signaling on CD4+ T cell activity. Other CD4+ T cells subset, Tregs, are a suppressive subset of T cells contribute to immune suppression, hindering anti-tumor immunity in the TME (98). Both IFN-I and IFN-γ significantly influence Treg function. IFN-I/IFNAR1 signaling induce the transformation of Tregs to fragile Tregs, a process mediated by downregulation of neuropilin-1 (Nrp1) expression, which is affected by IFNAR1-p38a signaling (99). This transformation compromises Treg stability, weakening their suppressive capacity in the TME (99). Similarly, IFN-γ also acts as Nrp1 antagonist that suppresses Treg proliferation and differentiation (100). Although Tregs survive in TME and typically form a feedback loop that limits IFN-γ production by NK cells and Teffs, IFN-γ disrupts this loop in tumors by inducing Treg fragility (101,102). This disruption boosts anti-tumor immunity and enhances the efficacy of therapies like anti-PD-1 (100). These insights underscore the complex interplay of IFN-I and IFN-γ in Treg regulation and indicate the potential for selectively targeting intratumoral Tregs to bolster anti-tumor immunity.

Similar to CD4+ T cells, CD8+ T cells, also known as CTLs, require IFN-Is for optimal differentiation, expansion, and effector function (103). IFN-Is enhances CTL cytotoxicity by promoting granzyme B production via STAT3 signaling and increasing CTL survival through genetic stabilization of IFNAR1 (104). Studies reveal that IFN-Is deficiency in CTLs undermines therapies like CAR T-cell and anti-PD-1 treatments (105), while local IFN-Is production via TLR9 agonists restores CTL numbers and function (106). During chronic viral infections, the early IFN-I signaling not only supports the priming of CD8+ T cells to survive and develop effector functions, but also programs these cells into a responsive memory population, including effector memory and central memory cells (107). Unlike classical memory T cells from acute infections, these cells often retain proliferative potential but exhibit exhaustion-linked phenotypic and functional changes (47). Exhausted T cells arise from memory precursors, with prolonged activation signals disrupting classical memory differentiation and promoting exhaustion (47). Prolonged IFN-I exposure further drives this process through IL-10, IDO, and PD-L1 expression, leading to terminal exhaustion (108,109). Some recent studies also report this exhaustion mechanism causing by IFN-I that may occur in the TME (110,111). Similarly, IFN-γ promotes CD8+ T cell differentiation, proliferation, and cytotoxicity by inducing granzymes and IL-2 receptor expression (112). Excessive and long-term exposure of IFN-γ signaling in the TME may lead to apoptosis of CD8+ T cells expressing high levels of IFNGR, thereby limiting their anti-tumor efficacy (112,113,114). However, recent study has shown loss of IFN-γ sensitivity on CD8+ T cells improves their effector function and contributes to successful anti-tumor immune response (114). Collectively, these findings emphasize that chronic exposure to IFN-Is or IFN-γ can drive CD8+ T cell exhaustion by upregulating immune checkpoints like PD-1, TIM-3, and LAG-3, ultimately suppressing their cytolytic potential (115,116).

DCs

In the TME, tumor-derived DNA and other DAMPs activate DCs through STING/IRF3 and TLR/IRF pathways, driving IFN-Is production (11,117). IFN-Is is critical for DC maturation, enhancing the expression of costimulatory molecules (CD40, CD80, CD86) and MHC class II, essential for robust antigen presentation (96,118). IFN-I exposure improves tumor antigen display and migratory capacity of DCs, which empower DCs to recruit and activate CD4+ and CD8+ T cells (119,120). Additionally, IFN-I-stimulated DCs produce high levels of IL-12 and IL-15, further amplifying downstream immune activation (121,122). Through STAT1- and IRF1-dependent pathways, IFN-γ increases MHC class I expression and promotes immunoproteasome formation, optimizing peptide presentation for CD8+ T cells (25). In vivo studies highlight that co-injection of IFN-γ and TLR ligands enhances DC activation, migration to lymph nodes, and subsequent T cell activity, emphasizing the synergistic effects of these signals on anti-tumor immunity (123).

Macrophages

Macrophages play a critical role in reprogramming the TME through IFN-Is and IFN-IIs (124). Both IFN-Is and IFN-γ increase macrophages activity by polarizing immature monocyte into mature anti-tumor phenotype (124). IFN-α signaling in TAMs also contributes to TME reprogramming by promoting DCs activation and boosting CD8+ T cell cytotoxicity against tumor cells (125). Emerging evidence also points out TAMs as a significant source of IFN-Is within the TME. TAMs from B16 melanoma express high levels of IFN-β after being treated with STING agonists (126). Similarly, TAMs expressing epidermal FA-binding proteins have been shown to produce high levels of IFN-β through upregulated lipid droplet formation, underscoring the importance of IFN-I production in TAMs (127). These studies suggest that TAMs might be a IFN-I source in the TME.

Several therapeutic strategies aim to amplify macrophage anti-tumor functions, including blocking CD47-SIRPα interactions enhances tumor cell phagocytosis by macrophages (128,129). Combining CD47/SIRPα inhibition with CD40 signaling activation via a SIRPα-Fc-CD40L fusion protein further increases IFN-I responses, driving effector T cell activation and suppressing tumor growth (130). Additionally, IFN-γ from Th1 cells boosts macrophage-mediated anti-tumor activity by inducing proteases, granzyme A/B, NK cell-related genes (e.g., NKG2D), and CXCL9 and CXCL10 secretion (131,132). Of note, the therapeutic efficacy of CD47-SIRPα blockade is highly dependent on tumor cell-intrinsic IFN-I signaling, but not IFN-II signaling. In ovarian cancer models, T cell-derived GM-CSF and IFN-γ enhance macrophage activation, IL-12p40 production, and antigen presentation, reinforcing immune responses (131). IFN-γ also stimulates macrophages to produce NO and directly lyse tumor cells (133). In a poorly immunogenic breast cancer mouse model, CSF-1R inhibitors are found to suppress macrophage-mediated immunosuppression by inducing IFN-I signaling and ISG expression, effectively synergizing with cisplatin therapy (134,135). Together, these findings underscore the dual role of IFNs in sustaining macrophage-mediated direct and immune-driven tumor cell death within the TME.

NK cells

NK cells, a critical component of innate immunity, are activated by cytokines such as IFN-I, IL-12, and IL-15 (136,137). In the TME, IFN-Is promote NK accumulation and activation via ISGs like CXCL10 and CCL5 (138). STING-induced IFN-Is production enhances NK cytotoxicity, crucial for anti-tumor immunity (139). Preclinical studies show that loss of IFN-Is receptor signaling in NK cells reduces their ability to mediate tumor cell lysis, leading to increased metastasis (140,141). Conversely, IRF7 overexpression in tumor cells boosts IFN-Is levels, inhibiting metastases through NK activation (142). IFN-γ also enhances NK cells function by upregulating CXCR3 ligands, facilitating NK cells recruitment to the TME (143,144). However, IFN-γ exposure may paradoxically increase PD-L1 expression on tumor cells, reducing their susceptibility to NK cells cytotoxicity (145). Studies suggest that while IFN-Is maintains NK function in chronic infections and tumors, IFN-γ’s effects on NK cytotoxicity depend on its influence on tumor immunogenicity (81,146).

THERAPEUTIC IMPLICATIONS AND MAJOR CHALLENGES

Therapeutically, targeting IFN-induced metabolic shifts could help fine-tune immune responses or counteract tumor progression. However, these effects are highly cell-type and context-dependent, influenced by factors like hypoxia, mTOR activation, and genetic variations. A deeper understanding of these diverse processes is essential for leveraging IFN signaling in disease contexts, balancing the benefits for immune activation against potential contributions to tumor progression or metabolic disorders.

Prolonged or dysregulated IFNs signaling can support tumor progression. Persistent IFN-γ signaling induces immune evasion by upregulating checkpoint molecules like PD-L1 and NOS2, contributing to resistance to immune checkpoint inhibitors (ICIs) (147). Low-dose of IFN-γ exposure has been linked to increased expression of intercellular adhesion molecule 1 and cancer stem cell (CSC) enrichment, while persistent signaling triggers epigenetic changes, such as enhanced STAT-1-associated chromatin accessibility, facilitating immune therapy resistance (148). Chronic IFN-γ signaling also promotes CD8+ T cells exhaustion and depletes stem-like CD8+ T cells, restricting anti-tumor immunity, and suggests that reducing CD8+ T cell sensitivity to IFN-γ could enhance the efficacy of T cell-based therapies (114). Additionally, IFN-γ promotes tumor metabolic reprogramming, EMT, enhances CSC properties, and drives metastasis, recurrence, and resistance to therapy (54,55,149). Targeting IFN-γ-STAT3-driven metabolic reprogramming in tumor cells could enhance T cell-mediated immunosurveillance and improve anti-tumor immune responses (54). In triple-negative breast cancer, IFNGR1 stabilization has been associated with increased tumor growth, metastasis, and poor survival outcomes, highlighting its potential pro-tumorigenic effects in certain contexts (150). In addition to the prolonged exposure of IFNs, resistance to IFNs often stems from genetic, epigenetic, and environmental alterations within the tumor and TME, which particularly represents an important issue in patients developed acquired resistance to immune checkpoint blockade therapy. Loss-of-function mutations in JAK1/2, STATs, and β2-microglobulin in cancer cells impair IFN-mediated signaling (151,152,153). Tumors also downregulate IFNAR or IFNGR1to hamper IFN activity (96,154). These resistance mechanisms diminish the efficacy of ICIs, chemotherapy, and radiation therapy, underscoring the need for innovative strategies. Therapies aimed at targeting IFN signaling—such as suppressing IFNAR1, targeting suppressors like SOCS1/3, or combining IFN-based approaches with ICIs or EMT inhibitors—show potentially promise effect (93,155,156). Moreover, tailoring treatments to tumor-specific IFN dynamics and reprogramming the TME to balance immune cell-driven IFN activity could also optimize therapeutic outcomes of IFNs in cancer therapy.

FUTURE DIRECTIONS AND CHALLENGES

Despite their therapeutic potential, IFN-based cancer therapies face challenges such as resistance and toxicity. The importance of advancing our knowledge of IFN-mediated processes and combine with new drug treatment is urgently needed. To address these challenges, researches should focus on developing strategies to overcome IFNs resistance and optimize its therapeutic benefits. Targeting negative regulators of IFNs signaling, such as SOCS1/3, and combining IFN-based therapies with ICIs or EMT inhibitors could enhance efficacy. Personalized approaches, guided by biomarkers and tumor-specific IFN signaling dynamics, may improve patient outcomes by guiding the treatments to individual needs. Reprogramming the TME to enhance IFN-mediated immune activation while minimizing pro-tumorigenic effects is another critical issue. Additionally, targeting IFN-induced metabolic reprogramming, such as manipulating glycolytic pathways, could fine-tune immune responses. Combining single-cell RNA sequencing and spatial transcriptomics will gain in unmasking the complexity of IFN signaling in the TME. Furthermore, combination therapies that integrate IFNs with other treatment to mitigate the harmful effects of chronic IFN exposure, such as epigenetic reprogramming, might offer promising directions for future research.

Abbreviations

Arg

arginase

CSC

cancer stem cell

DAMP

damage-associated molecular pattern

DC

dendritic cell

EMT

epithelial-to-mesenchymal transition

FA

fatty acid

GAS

interferon-γ-activated site

ICI

immune checkpoint inhibitor

IDO

indoleamine-2,3-dioxygenase

IFNAR

type I interferon receptor

IFNGR

type II interferon receptor

IFN-Is

type I interferons

IFN-IIs

type II interferons

IFN-IIIs

type III interferons

iNOS

inducible nitric oxide synthase

ISG

interferon-stimulated gene

MDSC

myeloid-derived suppressor cell

NO

nitric oxide

Nrp1

neuropilin-1

OXPHOS

oxidative phosphorylation

PRR

pattern recognition receptor

STING

Stimulator of Interferon Genes

TAM

tumor-associated macrophage

T-bet

T-box transcription factor

TME

tumor microenvironment