The earliest immunotherapies developed were cytokine-based. Cytokines serve as “messengers” orchestrating cellular interactions within the immune system in response to stresses. Interferon type 1 (IFN-I) and interleukin-2 (IL-2) were the first cytokines to be identified and FDA-approved by the end of the 20th century (7–10). Several additional cytokines followed the same path but displayed toxic side effects that prompted researchers to explore other immune components for cancer therapy.

Another category of agents is based on oncolytic viruses, which take advantage of the weakened antiviral defenses of cancer cells. Genetic engineering has led to the approval of four oncolytic virus therapies worldwide, used against melanoma, head and neck cancers, and malignant glioma (11–14).

Cancer vaccines using tumor-specific antigens to elicit T-cell-mediated anti-tumor immune responses emerged as a less toxic alternative than cytokines. This concept initially arose from the use of Bacillus Calmette-Guérin (BCG), a weakened form of Mycobacterium bovis, as a vaccine to reduce tumor growth (15–17). However, it was not until 2010 that the FDA approved sipuleucel-T, the first cancer vaccine (18). Advances in cancer immunotherapy have led to next-generation vaccines using mRNA technology and tumor neoantigens.

With the identification of tumor antigens capable of mediating T-cell responses, antibody-based therapies emerged as a new possible approach. These antibodies either bind tumor cell antigens to mark them for immune destruction or target immune cells to activate them against cancer cells. Antibodies targeting immune cell receptors began with the discovery of 4-1BB, a T-cell co-stimulatory receptor (19–21). This discovery paved the way for monoclonal antibodies developed to amplify T-cell responses. On the other hand, the identification of immune checkpoints (IC) revolutionized immunotherapy with immune checkpoint inhibitors (ICIs) designed to block inhibitory receptors on immune cells and reactivate anti-tumor immunity (3). CTLA-4, PD-1 receptor and its ligand, PD-L1, are the most common checkpoint molecules therapeutically targeted by approved therapies for various cancers (22–32). After them, other T cell surface receptors, such as LAG-3 and TIM-3, also became target for ICIs (1). To date, 128 ICIs have already been approved, representing 81% of all cancer immunotherapies (6). Bispecific antibodies are the next generation of antibody-based therapies combining checkpoint blockade with targeted co-stimulation of T cells. So far, 8 bispecific antibodies have received FDA approval and are emerging as important immunotherapies (6).

More recently, the power of T cells to make potent cancer-targeting therapies led to the development of adoptive cell therapies. They utilize patients’ or donors’ immune cells, which are collected, sometimes genetically engineered, expanded, and reinfused to treat cancer. These personalized treatments began with the use of tumor-infiltrating lymphocytes (TILs) (33). However, the identification of T-cell receptor (TCR) genetic sequences enabled the development of TCR-engineered T cells and chimeric antigen receptor (CAR) T cells (34, 35). The challenge of short-lived responses was addressed by the addition of co-stimulatory domains like CD28 or 4-1BB, which enhanced durability and potency (36–38), leading to several FDA approvals for hematological malignancies (39–41) and solid tumors (42). Importantly, CAR technology has lately expanded beyond T cells to natural killer (NK) cells and macrophages, offering off-the-shelf products accessible to more patients (43).

However, despite notable successes, immunotherapies still fail to benefit a large number of patients, mainly due to tumor-intrinsic heterogeneity and tumor-extrinsic factors like the immunosuppressive tumor microenvironment (TME). Hence, unlocking immunotherapy’s full potential requires strategies to overcome such resistance mechanisms. Resistance can be broadly categorized as primary, adaptive, or acquired, each shaped by distinct intrinsic and extrinsic processes that undermine antitumor immune responses (44). Primary resistance describes the absence of clinical benefit from the onset of treatment, occurring when tumors fail to trigger an effective immune response despite therapy (45). In contrast, adaptive resistance emerges under therapeutic pressure, as tumor cells dynamically reprogram immune-recognition pathways to evade immune destruction. This process reflects the complex crosstalk between tumor and immune cells within the TME, as well as the connection between intrinsic and extrinsic factors (44, 46). Finally, acquired resistance denotes the loss of therapeutic benefit typically due to epigenetic remodeling, epithelial–mesenchymal transition (EMT), stemness induction, and mitochondrial or caspase alterations. Altogether, these resistance mechanisms highlight the diverse ways tumors escape immunotherapy, and they encompass both tumor-intrinsic drivers and microenvironmental influences.

Among these drivers, the MYC oncogene has emerged as a key orchestrator of immune evasion and immunotherapy resistance. Through its key role in tumor proliferation, metabolism, and TME remodeling, MYC shapes both intrinsic tumor properties and the extrinsic immune landscape. Moreover, MYC deregulation emerges as an oncogenic feature across the different tumor types with approved immunotherapies (Table 1), including melanoma (47–49), renal cell carcinoma (50), esophageal cancer (51), glioblastoma (52), head and neck squamous cell carcinoma (53), prostate cancer (54), breast cancer (55, 56), endometrial cancer (56), non-small-cell lung cancer (57, 58), small-cell lung cancer (59), hepatocellular carcinoma (60), colorectal cancer (57, 61, 62), sarcoma (63–65) and hematological malignancies (66–69). This shared MYC dependency strengthens its potential as a therapeutic target to overcome immunotherapy resistance. Therefore, this review discusses MYC’s role in tumorigenesis, with a particular focus on how MYC rewires antitumor immunity and contributes to immunotherapy failure and highlights therapeutic avenues to target MYC-driven resistance.

MYC is a central orchestrator of tumor immune evasion and a key mediator of resistance to IO therapies (57, 90, 115, 116). In fact, MYC modulates cytokine signaling, upregulates molecules that help cancer cells evade immune surveillance and secret compounds that recruit immunosuppressive and tumor-promoting cells (Figure 2).

MYC deregulation rewires tumor-intrinsic signaling pathways to escape immune surveillance, while also remodels the TME to suppress antitumor immunity and reduce immunotherapy efficacy. It directly influences intrinsic and extrinsic mechanisms in primary, adaptive or acquired resistance to immunotherapy (Figure 3).

Indirect MYC inhibitors exploit vulnerabilities in MYC transcription, translation, or stability. There are clear advantages to these strategies, as some of the compounds used were originally developed for other oncogenic targets and are already available or clinically advanced. However, they may not be ideal for specific MYC inhibition due to limited selectivity and potential off-target effects. These indirect approaches are numerous and mechanistically diverse, and while they have been recently reviewed elsewhere (96, 100, 223–225), several stand out as particularly relevant in the context of immunotherapy resistance and are discussed below. Compounds with ongoing clinical evaluation are summarized in Table 2, while those with either completed, inactive, or discontinued trials are described in the text for completeness.

G-quadruplex stabilizers such as CX-5461 (226) and CX-3543 (227) repress MYC transcription by stabilizing secondary DNA structures within the MYC promoter and ribosomal DNA, leading to replication stress, type I interferon activation, and increased tumor immunogenicity (228). Moreover, CX-5461 combined with anti-PD-1 or anti-PD-L1 enhanced therapeutic efficacy in CRC preclinical models (228, 229). CX-5461 has received FDA Fast Track designation and is being evaluated in multiple completed and ongoing phase I/II clinical trials, underscoring its therapeutic promise (230). Nonetheless, both agents suffer from off-target effects and unfavorable pharmacokinetics, with CX-3543 failing in clinical trials owing to limited bioavailability and strong plasma protein binding (227). Similarly, clinical trials with APTO-253, another G4-stabilizing agent, were halted due to manufacturing and solubility issues that led to a prolonged clinical hold, and ultimately the program was terminated due to insufficient clinical activity in the Phase I clinical trial (231). Others like IZCZ-3, QN-1, and IZTZ-1showed anticancer activity in preclinical models (232).

Similarly, CDK7 inhibitors [e.g. CT7001 (233), SY-1365 (234), SY-5609 (235), LY3405105 (236)) and CDK9 inhibitors (e.g. KB-0742 (237), CYC065 (238), dinaciclib (239), enitociclib (240)] suppress MYC transcriptional activity by blocking transcriptional initiation or elongation (241–244). Because inhibition of these transcriptional CDKs preferentially affects short-lived transcripts, including those encoding anti-apoptotic and cell cycle regulatory proteins, targeting this kinase family offers a rational strategy to blunt MYC-dependent transcriptional amplification (244). In addition to their direct antiproliferative effects, CDK7/9 blockade has been shown to downregulate PD-L1 expression, induce genomic instability triggering type I interferon responses, and enhance tumor immune infiltration, thereby sensitizing MYC-driven tumors to immune checkpoint blockade (245–248). For example, in SCLC, treatment with the CDK7i YKL-5–124 elicited immune response signaling and promoted activation of anti-tumor T cells and co-administration of YKL-5–124 with anti–PD-1 therapy led to a significant increase in overall survival compared with monotherapy (246). Similarly, in hepatocellular carcinoma (HCC), mice receiving the combination of a CDK9 inhibitor and an anti-PD-L1 antibody developed significantly smaller tumors and showed prolonged survival compared with those treated with either agent alone (247). Although preliminary pharmacodynamic data showing effective reduction of MYC expression are encouraging, as regulators of transcription, CDK7/9 inhibitors carry the risk of broad off-target effects by interfering with global transcription, which may constrain their therapeutic window. Ongoing clinical trials will be key to determine whether these inhibitors can selectively target MYC-driven cancers while maintaining an acceptable safety profile.

Other kinase inhibitors such as Aurora kinase A (Alisertib (249), MK-5108 (250), TAS-119 (251)) and PLK1 inhibitors (onvansertib (252), volasertib (253), CYC140 (254)) destabilize MYC at the post-translational level, triggering mitotic arrest and apoptosis (249, 250, 255), possibly enhancing immune recognition. Mechanistically, Aurora A kinase interacts with and stabilizes MYC by preventing its ubiquitin-mediated degradation; thus, Aurora A inhibition promotes MYC destabilization and proteasomal turnover (255, 256). Similarly, PLK1 inhibition interferes with MYC phosphorylation events required for its stability and transcriptional activity (257). By promoting MYC degradation, these compounds attenuate MYC-driven transcriptional programs and restore anti-tumor immune responses when combined with immunotherapies. For instance, alisertib has been shown to remodel the tumor immune microenvironment by depleting tumor-promoting myeloid populations and enriching cytotoxic T lymphocytes (258, 259). Moreover, it showed synergistic therapeutic effects when combined with PD-L1 and CTLA-4 blockade in models of breast (258) and papillomavirus-driven cancers (259). In the same line, PLK1 inhibitors have also been shown to exert synergistic effects in combination with immunotherapy (260). In vivo studies demonstrated that combining a PLK1 inhibitor with PD-L1 blockade markedly reduced tumor growth compared to either agent alone in both lung (261) and pancreatic cancers (262).

Another indirect strategy to inhibit MYC involves PP2A activators (e.g., DT-061 (263), LB-100 (264)), which restore phosphatase activity lost in MYC-driven cancers. Activation of PP2A promotes dephosphorylation of MYC at Ser62, leading to its proteasomal degradation (265, 266). By reducing MYC levels in this way, PP2A activators can restore antitumor immune surveillance and enhance tumor sensitivity to immunotherapies (267). In CRC, LB-100 treatment caused exon skipping and increased alternative splicing, inducing neoantigen expression (268) and, in a glioblastoma model, enhanced antitumor efficacy of PD-1 blockade (269).

BET inhibitors (e.g., JQ1 (270), OTX015 (271), CPI-0610 (272), GSK525762 (273, 274), BMS-986158 (275), INCB057643 (276), AZD5153 (277), ZEN-3694 (278)) block BRD4-dependent chromatin remodeling and MYC transcription, thereby restoring interferon signaling and antigen presentation, and are under active investigation in combination with immunotherapy (270, 279, 280). JQ1 was the first-in-class compound to establish proof-of-concept for BET inhibition in cancer therapy; however, its suboptimal in vivo pharmacokinetic profile has prevented its advancement to clinical trials. Despite this, preclinical studies have shown that JQ1 enhances antitumor immunity by upregulating MHC-I expression, downregulating PD-L1, and synergizing with anti-PD-1/L1 therapies across multiple cancer models (281–286). Despite the promising preclinical activity of BET inhibitors, clinical translation has proven challenging. The majority of compounds have been discontinued or had their clinical trials terminated due to limited efficacy or tolerability issues. Furthermore, BET inhibitors downregulate other genes beyond MYC, suggesting that their anticancer effects are not solely MYC-dependent (66). Only a few agents, such as AZD5153 and ZEN-3694, remain under active clinical investigation. Notably, in preclinical models, AZD5153 has been shown to promote antitumor immunity by depolarizing immunosuppressive M2 macrophages (287) and increasing sensitivity to anti-PD-L1 therapy (288).

Finally, epigenomic modulation has also been pursued to indirectly target MYC. OTX-2002 is a first-in-class mRNA-based epigenomic modulator that represses MYC pre-transcriptionally by establishing targeted epigenetic marks. Preclinical studies in HCC demonstrated strong anti-tumor activity, downregulation of PD-L1 and improved therapeutic activity when combined with anti-PD-(L)1 antibodies. Interestingly, the therapeutic effect was accompanied by a reduction of Tregs in the TME (289). Preliminary clinical data indicate a favorable safety profile and on-target epigenetic effects (290).

The challenges of indirect MYC inhibitors have driven the pursuit of direct MYC-targeting approaches designed to engage the oncoprotein itself, offering a more selective and mechanistically precise means of inhibiting MYC and restoring tumor immune surveillance. Direct MYC inhibitors aim to disrupt MYC function at the protein level, either by preventing its dimerization with MAX, blocking DNA binding, or promoting MYC degradation (100, 223–225). Such strategies once thought unfeasible have now entered preclinical and early clinical evaluation, showing promising signs of efficacy and tolerability. The following section highlights the most advanced and promising direct MYC inhibitors, with those currently undergoing clinical testing summarized in Table 3.

The most advanced direct MYC inhibitor in clinical trials is OMO-103, a MYC dominant negative. It is the clinical formulated drug product derived from Omomyc, a 91 amino acid mini-protein based on the MYC b-HLH-LZ domain engineered with four amino acid substitutions that alter its dimerization properties (292). Omomyc can form both homodimers and heterodimers with MYC and MAX. While Omomyc/Omomyc and Omomyc/MAX dimers bind E-box sequences as transcriptionally inactive complexes, Omomyc/MYC dimers cannot bind DNA (292, 293). Through this dual mechanism of action - sequestering MYC away from DNA and occupying its target promoters with repressive complexes - Omomyc acts as a dominant-negative inhibitor of MYC transcriptional activity. Extensive preclinical studies have demonstrated that Omomyc-mediated MYC inhibition is both highly effective and well tolerated, suppressing tumor growth and inducing regression across multiple cancer types, irrespective of tissue origin or oncogenic driver (49, 52, 113, 294–298). In line with MYC’s capacity to drive tumorigenesis through both cell-intrinsic and -extrinsic mechanisms, Omomyc exerts dual anticancer actions directly suppressing tumor cell growth while simultaneously reshaping the surrounding microenvironment. For example, Omomyc treatment in a KRAS-driven NSCLC mouse model increased immune infiltration, notably recruiting T cells to the tumor site (295). Additionally, a phylomeric form of Omomyc reduced PD-L1 expression in a model of TNBC (299). Beyond cancer models, Omomyc-mediated c-MYC inhibition in mature macrophages triggered extensive transcriptomic remodeling in a tuberculosis model, upregulating key inflammatory pathways such as IFNγ, TNFα, and IFNα responses, and underscoring its broad immunomodulatory potential (300). Together, these effects contribute to a more immunostimulatory tumor milieu and may sensitize tumors to immune checkpoint blockade. OMO-103 is now being evaluated in Phase Ib/II clinical trials.

IDP-121 and IDP-410 are next-generation stapled peptide MYC inhibitors that target distinct members of the MYC oncogene family, c-MYC and N-MYC respectively. Both compounds disrupt MYC’s interaction with MAX and promote MYC monomer degradation. IDP-121 has demonstrated antitumor activity across multiple preclinical hematologic and solid tumor models (301) and has recently entered clinical evaluation, while IDP-410 reduced growth and vascularization in vivo in a glioblastoma mouse model, suggesting a link between N-MYC function and mesenchymal or angiogenic programs (302). To date, no further public data have been released for either compound, and their potential effects on the tumor immune microenvironment remain unexplored.

Other small molecules have been developed to target the MYC–MAX interaction, including MYCi361 and its optimized analogue MYCi975. These compounds disrupt MYC–MAX dimerization and promote phosphorylation of MYC at T58, leading to proteasome-mediated degradation (303). In preclinical models, MYCi361 suppressed tumor growth and enhanced immune infiltration, increasing CD3⁺ T cells, IFNγ⁺ CD4⁺ and CD8⁺ T cells, TNFα⁺ CD8⁺ cells, dendritic cells, and NK cells, while upregulating PD-L1 and sensitizing tumors to anti-PD-1 therapy. Although MYCi361 displayed a narrow therapeutic window, MYCi975 showed improved tolerability while retaining immunomodulatory activity, including increased pT58, PD-L1 expression, and enhanced infiltration of T, B, and NK cells. Combination therapy with anti-PD-1 yielded synergistic tumor suppression (303). Similarly, in TNBC and head-and-neck cancer mouse models, MYCi975 increased CD8⁺ T-cell infiltration (304, 305), and in TNBC, co-treatment with anti-PD-L1 produced stronger tumor growth inhibition than either agent alone (304). An optimized version of MYCi975 is expected to enter clinical evaluation in the near future (306).

Other direct MYC-targeting strategies aim to destabilize MYC by promoting its degradation. One such approach involves the small-molecule degrader WBC100, which targets MYC proteostasis rather than dimerization. However, for MYC, this strategy is challenging due to the protein’s inherently short half-life and continuous synthesis in cancer cells, which could necessitate frequent or sustained dosing of any therapy that relies solely on MYC degradation. In preclinical models, oral WBC100 administration markedly reduced MYC protein levels, inhibited tumor growth, and prolonged survival without notable toxicity (307). The compound is currently being evaluated in a Phase I clinical trial for patients with advanced solid tumors overexpressing c-MYC. To date, however, no clinical data or evidence regarding its potential effects on the tumor immune microenvironment have been reported.

Alternative strategies to inhibit MYC focus on blocking its mRNA translation using antisense oligonucleotides or RNA interference (RNAi) technologies such as siRNA or shRNA. Among these, DCR-MYC, a MYC-targeting siRNA, advanced to Phase I/II clinical trials but was discontinued due to insufficient gene-silencing efficacy (308). Although the immunological effects of MYC-targeted RNA therapies have not been directly characterized, MYC silencing is expected to indirectly enhance antitumor immunity by reversing MYC-driven immunosuppression. Thus, future studies integrating RNA-based MYC inhibition with immune checkpoint blockade could provide valuable insights into their potential immunomodulatory synergy.

While this review focuses on the immunomodulatory effects of MYC inhibition, it is important to note that many of the compounds discussed above also impact classical tumor-intrinsic mechanisms of oncogenesis induced by MYC. MYC-targeted therapies can suppress proliferation, induce apoptosis, and impair metabolic programs that are critical for tumor growth and survival. For example, CDK7/9 inhibitors, Aurora kinase A inhibitors, and direct MYC inhibitors such as Omomyc not only enhance tumor immunogenicity but also reduce MYC-driven transcriptional amplification of genes involved in cell cycle progression, ribosome biogenesis, and DNA replication. However, the extent to which each strategy affects the full spectrum of MYC functions varies, reflecting differences in mechanism of action and target specificity. Understanding how MYC inhibition balances tumor-intrinsic and immune-mediated effects will be crucial for choosing the most optimal combination therapies.