The Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions

Abstract

Cancer continues to be a significant global health issue, influenced by genetic mutations and external factors like carcinogenic exposure, lifestyle choices, and chronic inflammation. The myelocytomatosis (MYC) oncogene family, including c-MYC, MYCN, and MYCL, is essential in the development, progression, and metastasis of various cancers such as breast, colorectal, osteosarcoma, and neuroblastoma. Beyond its well-known roles in cell growth and metabolism, MYC significantly shapes the tumor immune microenvironment (TIME) by altering immune cell dynamics, antigen presentation, and checkpoint expression. It contributes to immune evasion by upregulating checkpoints such as programmed death-ligand 1 (PD-L1) and cluster of differentiation (CD)47, suppressing antigen-presenting major histocompatibility complex (MHC) molecules, and promoting the recruitment of suppressive immune cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). While direct targeting of MYC has proven challenging, recent advances in therapeutic strategies, including MYC-MYC-associated factor X (MAX) dimerization inhibitors, bromodomain and extra terminal domain (BET) and cyclin dependent kinase (CDK) inhibitors, synthetic lethality approaches, and epigenetic modulators, have shown promising results in preclinical and early clinical settings. This review discusses MYC’s comprehensive impact on TIME and examines the promising therapeutic strategies of MYC inhibition in enhancing the effectiveness of immunotherapies, supported by recent preclinical and clinical findings.

Graphical abstract

Keywords

MYC / tumor immune microenvironment / immunotherapy / cancer / oncogene

1. Introduction

In 2022, approximately 20 million new cancer cases and 9.7 million cancer-related deaths were reported globally, with projections indicating a sharp rise to 35 million new cases by 2050 [1]. In the United States alone, the American Cancer Society estimates around 2 million new cancer cases and 600,000 cancer deaths in 2024 [2]. This alarming burden underscores the urgent need for innovative therapeutic strategies to improve patient outcomes and reduce mortality rates. Cancer progression is a multifactorial process involving a complex interplay of genetic mutations and environmental influences. Among these, intrinsic alterations in oncogenes and tumor suppressor genes are pivotal, as they deregulate fundamental cellular processes such as cell proliferation, apoptosis, and immune surveillance, thereby driving malignant transformation and disease progression [3, 4]. One of the most critical oncogene families implicated in cancer is the myelocytomatosis (MYC) family, which comprises three closely related members: c-MYC, MYCN, and MYCL [5, 6]. These oncogenes stand out due to their frequent dysregulation and their broad influence on cancer biology across a wide range of malignancies, including neuroblastoma, breast cancer, colorectal cancer, osteosarcoma and small-cell lung cancer (SCLC) [7, 8, 9]. MYC proteins are transcription factors that govern vital cellular processes, including metabolism, protein synthesis, and genomic integrity. Their overexpression or amplification is often associated with aggressive tumor phenotypes, poor prognosis, and resistance to conventional therapies [10, 11].

MYC proto-oncogenes are central regulators of fundamental cellular processes, including cell growth, proliferation, metabolism, and differentiation [12, 13, 14]. Dysregulated MYC signaling is a hallmark of many human cancers, driving malignant transformation and tumor progression. Beyond driving intrinsic tumor growth, MYC profoundly influences the tumor microenvironment (TME), particularly the tumor immune microenvironment (TIME) [15, 16, 17, 18]. The TME is a dynamic and complex milieu consisting of tumor cells, immune cells (e.g., macrophages, dendritic cells, T cells, B cells, etc.), smooth muscle cells, endothelial cells, and cancer-associated stromal cells, including cancer-associated fibroblasts (CAFs) [19, 20, 21, 22, 23]. These components collectively shape tumor progression, immune evasion, and therapeutic response [21]. Within this context, MYC-driven tumors exploit the TIME by upregulating immune checkpoint proteins such as programmed death-ligand 1 (PD-L1) and cluster of differentiation (CD)47, which suppress antitumor immune responses [17]. In addition, MYC promotes the recruitment of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while simultaneously downregulating antigen presentation pathways, further facilitating immune evasion [17]. These MYC-induced alterations create an immunosuppressive environment that promotes tumor survival and growth while also limiting the efficacy of immunotherapeutic interventions [24, 25, 26].

While immune checkpoint blockade (ICB) therapies targeting the programmed death (PD)-1/PD-L1 and cytotoxic T-lymphocyte-associated protein (CTLA)-4 pathways have transformed the landscape of cancer treatment, their effectiveness in MYC-overexpressing tumors remains suboptimal due to the immunosuppressive nature of the TIME [27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37]. MYC is a highly attractive therapeutic target in cancer due to its central role in regulating key pathways and several preclinical tumor models have demonstrated that turning off MYC expression leads to tumor regression, providing proof of concept that pharmacological targeting of MYC could effectively inhibit tumor growth [38, 39, 40, 41, 42]. However, direct targeting of MYC with small-molecule inhibitors poses significant challenges. MYC is intrinsically disordered, lacking a well-defined hydrophobic pocket or groove suitable for high-affinity binding by low molecular weight compounds [11, 43]. Unlike other oncogenic drivers, MYC lacks enzymatic activity, making it unsuitable for inhibition by conventional enzyme-targeting drugs. Preclinical studies have shown that MYC inhibition can reprogram the TIME, enhance immune cell infiltration, and restore sensitivity to ICB therapies. Combining MYC inhibition with ICB therapies has emerged as a promising strategy to synergistically boost antitumor immune responses and improve clinical outcomes [38, 44, 45].

This review aims to provide a comprehensive analysis of MYC’s role in regulating the TIME, with a focus on its mechanisms of immune evasion, therapeutic resistance, and tumor progression. Additionally, we explore emerging therapeutic strategies targeting MYC, including bromodomain and extra terminal domain (BET) inhibitors, cyclin dependent kinase (CDK) inhibitors, synthetic lethality approaches, and epigenetic modulators. By highlighting recent advancements and ongoing challenges, we aim to propose future research directions in this rapidly evolving field of cancer therapy.

2. MYC and Tumor Immune Microenvironment Regulation

MYC plays a central role in immune evasion by regulating key immune checkpoints, suppressing antigen presentation, and fostering an immunosuppressive TME. In MYC-driven tumors, upregulation of immune checkpoints like PD-L1 and CD47 impairs T cell function and promotes immune tolerance [46]. Fig. 1 illustrates how MYC-driven tumors regulate immune cells in the TME, collectively creating a TIME that resists immune surveillance and therapy.

2.1 MYC-Mediated Regulation of Immune Checkpoints

MYC plays a critical role in immune evasion by directly modulating the expression of key immune checkpoint molecules, encompassing both adaptive and innate immune regulators, thereby fostering an immunosuppressive TME. Among the adaptive immune checkpoints, PD-L1 is one of the most critical targets of MYC. By directly binding to the promoter region of PD-L1, MYC drives its transcriptional activation, leading to T cell exhaustion and reduced cytokine production. This mechanism has been observed in esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC) [47, 48, 49]. In oxaliplatin-resistant HCC, MYC enhances PD-L1 expression and recruits polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) through C-C motif chemokine ligand (CCL)5 secretion, further amplifying immune suppression and therapeutic resistance. Notably, MYC depletion in preclinical models reduces PD-L1 expression, restores CD8⁺ T cell activity, and sensitizes tumors to chemotherapy [50, 51]. In addition to PD-L1, MYC regulates innate immune checkpoints, particularly CD47, which acts as a “do not eat me” signal by binding to signal regulatory protein alpha (SIRP\alpha) on macrophages, preventing phagocytosis. MYC directly promotes CD47 expression by binding to its promoter. However, the extent of MYC’s regulation of CD47 varies across tumor types. For instance, MYC promotes CD47 expression in SCLC cells by binding to and inhibiting histone deacetylases (HDAC)1 activity, which likely results in a more open chromatin structure near the CD47 promoter facilitating transcriptional activation and increased expression of CD47. This mechanism highlights a novel, indirect regulatory pathway distinct from direct promoter binding. Additionally, MYC regulates other immune-related ligands, such as major histocompatibility complex (MHC) class I polypeptide-related sequence A and B (MICA/B), PD-L1, and CD155, through complex and potentially opposing interactions with HDAC1 [17, 52]. MYC-driven metabolic reprogramming significantly contributes to immune evasion by modulating the TME. In non-small cell lung carcer (NSCLC), MYC promotes tumor-specific acetate uptake, leading to elevated acetyl-CoA levels [50]. Elevated acetyl-CoA facilitates the acetylation of MYC at lysine 148 (K148), this acetylation stabilizes MYC by preventing its degradation, thereby increasing its protein levels. Stabilized MYC acts as a transcription factor and upregulates several genes, including the aforementioned PD-L1, glycolytic enzymes, and monocarboxylate transporters, enhancing immune suppression. Inhibition of acetate metabolism has been shown to improve the efficacy of anti-PD-1 therapy by reducing PD-L1 expression and increasing CD8⁺ T cell infiltration [50]. Additionally, in multiple myeloma (MM), delta-N p (DNp)73, a transcriptional activator of MYC, drives the expression of PD-L1 and CD47, further promoting immune evasion. Blockade of these checkpoints using anti-PD-L1 and anti-CD47 antibodies has demonstrated significant improvement in macrophage and T cell-mediated tumor clearance in MM and SCLC [52, 53].

Given the central role of MYC in regulating immune checkpoints, combining immune checkpoint blockade with MYC-targeted therapies has emerged as a promising approach. For example, in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated pancreatic ductal adenocarcinoma (PDAC), silvestrol, a eukaryotic initiation factor 4A (eIF4A) inhibitor that blocks MYC translation, synergized with anti-PD-1 therapy to suppress tumor growth by reducing MYC-driven PD-L1 expression and macrophage recruitment [54]. Additionally, an eIF4A inhibitor enhances the efficacy of KRAS G12C inhibitors in NSCLC by suppressing B-cell lymphoma (BCL)-2 family proteins, with MYC overexpression increasing sensitivity to this combination, highlighting a promising therapeutic strategy for KRAS-mutant NSCLC [55]. Targeting the inhibitor of DNA-binding 1 (ID1)/MYC axis in HCC similarly reduced PD-L1 expression and MDSCs infiltration, enhancing immune responses and improving sensitivity to chemotherapy and checkpoint inhibitors [49]. These findings highlight the potential of combining MYC inhibition with immune checkpoint blockade to enhance therapeutic outcomes across diverse cancer types. The combination of MYC inhibition and immune checkpoint blockade, specifically anti-PD-L1, significantly enhances tumor regression and extends survival in MYC-driven triple-negative breast cancer (TNBC) [56].

2.2 MYC-Mediated Suppression of Antigen Presentation and its Therapeutic Implications

MYC-mediated suppression of antigen presentation is a key mechanism by which tumors evade immune surveillance [57]. MYC represses the expression of critical components of the antigen presentation machinery (APM), such as MHC class I molecules and transporter associated with antigen processing (TAP) transporters, through transcriptional regulation and post-translational modifications like small ubiquitin-like modifier (SUMO)ylation [56, 58]. This suppression reduces the tumor’s visibility to cytotoxic T cells, facilitating immune escape. Therapeutically, targeting MYC or its downstream pathways could restore APM function and enhance the efficacy of immunotherapies, such as immune checkpoint inhibitors, by increasing tumor immunogenicity and improving T cell-mediated tumor clearance.

2.2.1 MYC-Mediated Antigen Presentation Suppression

MYC-driven tumors employ a critical immune evasion strategy by suppressing the APM, which is essential for cytotoxic T lymphocytes (CTLs) to recognize and eliminate tumor cells. The APM involves major histocompatibility complex class I (MHC-I) molecules, which present intracellular peptides, including tumor-derived neoantigens, on the cell surface to CTLs. MYC overexpression consistently downregulates MHC-I and other APM components, impairing antigen presentation and limiting immune detection [57]. In human melanoma and rat neuroblastoma models, MYC-driven MHC-I downregulation correlated with reduced tumor immunogenicity and increased tumor growth [58, 59]. In TNBC, elevated MYC expression was linked to reduced MHC-I levels. However, restoring interferon signaling increased MHC-I expression, reversing MYC-driven immune evasion and promoting tumor regression [56]. In addition to MHC-I suppression, MYC-driven tumors impair the MHC-II pathway, crucial for activating CD4⁺ T helper cells. In BCL, MYC overexpression downregulates MHC-II and associated APM components, limiting CD4⁺ T cell-mediated antitumor responses. Importantly, pharmacological inhibition of MYC restores MHC-II expression and enhances tumor cell recognition by CD4⁺ T cells, demonstrating MYC’s influence on both arms of antigen presentation [57]. MYC also inhibits dendritic cell (DC)-mediated cross-presentation by upregulating immune checkpoint proteins CD47 and PD-L1. CD47 interacts with SIRP\alpha on DCs, reducing their ability to engulf tumor cells and present antigens, thereby weakening tumor-specific T cell activation. MYC suppression restores antigen uptake by DCs, enhances cross-presentation, and promotes robust adaptive immune responses [17, 60].

Several mechanisms contribute to MYC-mediated suppression of the APM machinery. In neuroblastoma, MYCN suppresses MHC class I expression by downregulating the p50 subunit of nuclear factor-kappa beta (NF-\kappa\beta), a key enhancer-binding transcription factor, thereby reducing enhancer activity and antigen presentation [61]. Additionally, MYCN amplification correlates with the loss of the modifier of methylation-1 (MEMO-1) locus, leading to hypomethylation of human leukocyte antigen (HLA) loci and further repressing MHC class I expression [62]. In nasopharyngeal carcinoma, MYC, induced by latent membrane protein 1 (LMP1) through the interleukin 6 (IL-6)/Janus kinase 3 (JAK3)/signal transducer and activator of transcription 3 (STAT3) pathway, counteracts LMP1-driven upregulation of HLA class I APM, ultimately resulting in its downregulation and facilitating immune evasion by impairing T cell recognition [63]. MYC plays a key role in suppressing the APM by modulating the SUMOylation pathway, a post-translational modification process that enhances immune suppression. Specifically, MYC promotes the SUMOylation of Scaffold Attachment Factor B (SAFB), which repress critical APM components, including HLA-A, HLA-B, beta-2-microglobulin (B2M), and TAP transporters. This MYC-SUMO axis reduces MHC-I surface expression, impairing antigen presentation and enabling immune evasion by limiting CD8⁺ T cell recognition of tumor cells [64]. In SCLC and neuroblastoma (NB), overexpressed MYCL and MYCN inhibit class II transactivator (CIITA) transcription by binding to its promoter, reducing MHC-I/II expression and impairing antitumor immunity [65]. Additionally, HASH-1 (Human Achaete-Scute Homologue-1), a neuroendocrine-specific transcription factor, is upregulated by MYCL. HASH-1 also binds to the CIITA promoter, further contributing to the repression of MHC expression. Anti-sense oligonucleotide experiments indicate that MYCL and MYCN regulate HASH-1 expression, placing MYC proteins upstream in the regulatory pathway. This MYC-HASH-1 axis creates a complex mechanism of CIITA suppression, enabling tumor cells to evade immune detection by reducing MHC expression, thereby contributing to immune escape in SCLC and NB [65]. In BCL, MYC downregulates key cofactors such as HLA-DM and gamma-interferon-inducible lysosomal thiol reductase (GILT), critical for HLA class II-mediated antigen presentation [57].

2.2.2 Therapeutic Approaches to Overcome MYC-Induced APM Suppression

Given the central role of MYC in suppressing antigen presentation, several therapeutic strategies have been explored. Recent research highlights the potential of combining PD-L1 and CTLA-4 blockade to recruit pro-inflammatory macrophages expressing CD40 and MHCII, partially reversing MYC-driven APM suppression [47]. Additionally, epigenetic modulators like HDAC inhibitors have shown efficacy in upregulating APM components, restoring immune visibility of MYC-driven tumors [66]. Preclinical studies further suggest that TAK-981, a SUMOylation inhibitor, can enhance antigen presentation by upregulating APM components, thereby sensitizing MYC-driven tumors to immune checkpoint blockade [64]. These approaches demonstrate the potential of targeting APM components to counteract MYC-induced immune suppression and improve therapeutic outcomes.

2.3 MYC Role in Immune Cell Infiltration to the Tumor Microenvironment

MYC activation significantly impacts immune cell recruitment and behavior within the TME, influencing various cancer types. In HCC, MYC overexpression drives the secretion of cytokines and chemokines, such as CCL5, which recruit PMN-MDSCs and Tregs, leading to T cell suppression and promoting tumor progression [49]. In osteosarcoma, elevated MYC expression is associated with reduced immune cell infiltration, including macrophages [67]. MYC inhibition using JQ-1 improves T cell recruitment and dendritic cell–T cell interaction, promoting tumor-specific CTL activation and enhancing the response to ICB therapy. Combining JQ-1 with anti-PD-1 therapy has shown promising potential in osteosarcoma treatment [45, 67]. In HCC, genetic alterations involving MYC significantly influence tumor-infiltrating T cells and their response to immune checkpoint inhibitors (ICIs). ‘Cold’ tumors with MYC alterations show improved sensitivity to anti-PD-1 therapy when combined with sorafenib, emphasizing the need for tailored therapeutic strategies based on genetic context [68]. Kortlever et al. [69] demonstrated that MYC activation in a KRAS-driven lung cancer led to the influx of immunosuppressive macrophages and the exclusion of T, B, and natural killer (NK) cells. Anti-PD-L1 therapy alone failed to induce tumor regression; however, combination therapy with MYC inhibitors restored immune cell infiltration and reduced tumor burden. MYC-driven tumors recruit tumor-associated macrophages (TAMs) that express PD-L1, further promoting T cell exhaustion and immune tolerance [17, 70].

These findings collectively highlight MYC’s pivotal role in regulating immune cell infiltration across different cancer types.

2.4 MYC Role in Immune Cell Response

Studies have demonstrated that MYC influences cancer development through various mechanisms, including cytokine modulation, immune checkpoint upregulation, and interaction with other oncogenic pathways [71, 72].

2.4.1 Suppression of Immune-Related Gene Expression

MYC-driven immune evasion occurs through multiple pathways, including suppression of immune-related gene expression. MYC facilitates immune evasion in ovarian cancer by downregulating nuclear receptor coactivator (NCOA)4, suppressing ferritin autophagy, and inhibiting ferroptosis. This prevents the release of immune-activating damage-associated molecular patterns (DAMPs) like high mobility group box (HMGB)1, thereby reducing immune cell infiltration and activation in the tumor microenvironment. By limiting immune responses, MYC promotes tumor immune evasion and progression [73]. Similarly, in TNBC, MYC hyperactivation represses stimulator of interferon genes (STING), a critical regulator of innate immunity. Reduced STING expression impairs downstream signaling pathways that produce key T cell chemokines, including CCL5, CXCL10, and CXCL11, thereby reducing the recruitment of tumor-infiltrating lymphocytes (TILs), such as cytotoxic CD8⁺ T cells, and contributing to tumor progression.

2.4.2 Crosstalk with Oncogenic Pathways

MYC collaborates with key oncogenic pathways, including KRAS, wingless-related integration site (WNT), alternate reading frame (ARF), and tumor protein p53 (TP53), to drive cancer progression and immune evasion [72, 74]. These oncogenes function synergistically, with KRAS inducing MYC expression and enhancing the translation of MYC and ARF6 mRNAs, which are tailored for robust expression during heightened energy production. MYC supports tumor metabolism by promoting mitochondrial biogenesis and oxidative phosphorylation, while ARF6 protects mitochondria from oxidative damage and facilitates invasion, metastasis, and immune checkpoint activation. This cooperative network is particularly prominent in aggressive cancers like pancreatic cancer and is further exacerbated by TP53 mutations [75]. The cooperation between MYC and oncogenic KRAS establishes a profoundly immunosuppressive tumor microenvironment by coordinating the transcriptional upregulation of cytokines (e.g., IL-6, IL-10, transforming growth factor \beta (TGF-\beta)) and chemokines (e.g., CCL9), promoting the recruitment of MDSCs, Tregs, and M2 macrophages. Concurrently, MYC and KRAS co-activate immune checkpoint pathways by enhancing PD-L1 and CD47 expression and suppressing MHC-I and type I interferon signaling, thereby attenuating cytotoxic T cell activity and facilitating immune evasion and resistance to immunotherapy [76]. In a mouse model of KRAS-driven lung adenomas, MYC co-activation accelerates the transition to invasive adenocarcinomas by creating an inflammatory, angiogenic, and immune-suppressed TME. MYC drives the production of epithelial-derived signals such as CCL9 and IL-23, which play distinct roles in immune regulation: CCL9 recruits macrophages, promotes angiogenesis, and mediates PD-L1-dependent T and B cell exclusion, while IL-23 excludes adaptive immune cells and NK cells. Blocking CCL9 and IL-23 significantly impairs MYC-driven tumor progression [69, 77]. MYC also stabilizes its expression in KRAS-mutant tumors through pathways like ERK1/2-mediated phosphorylation at serine 62, further enhancing its oncogenic and immunosuppressive effects [78]. In various cancers, including breast, colorectal, and HCC, aberrant MYC activation is often driven by upstream pathways like WNT/\beta-catenin signaling, which enhances MYC transcription through distal WNT responsive elements (WREs) via chromatin looping [79, 80, 81, 82, 83]. Furthermore, MYC establishes a feedforward circuit with WD repeat and SOCS box containing protein 1 (WSB1), where WSB1 stabilizes \beta-catenin and promotes MYC transactivation, amplifying its oncogenic activity [81]. Additionally, the WNT/\beta-catenin signaling pathway enhances MYC mRNA stability by modulating N⁶-methyladenosine (m6A) methylation levels through the regulation of FTO (fat mass and obesity-associated protein). Specifically, WNT signaling induces the binding of Enhancer of Zeste Homolog 2 (EZH2) to \beta-catenin, which increases trimethylation of histone H3 at lysine 27 (H3K27me3) marks on the FTO promoter, leading to its transcriptional repression. The downregulation of FTO, an m6A demethylase, results in an increase in m6A modification on MYC mRNA. This modification promotes the recruitment of YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), an m6A reader protein, enhancing the translation of MYC mRNA and ultimately increasing MYC protein levels [84]. Notably, MYC/\beta-catenin cooperation downregulates the chemokine CCL5, impairing dendritic cell recruitment and T cell activation. Inhibiting both WNT/\beta-catenin and MYC has been shown to reduce PD-L1 expression and restore antitumor immunity in preclinical models [83]. The MYC-p53 feedback loop plays a crucial role in maintaining T cell homeostasis by balancing proliferation and cytotoxic function. Elevating p53 levels suppresses MYC expression and reduces proliferation, while MYC inhibition downregulates p53 through reduced p14ARF, with both mechanisms inducing cell cycle arrest and apoptosis without impairing T cell cytotoxicity [85]. These findings underscore the crosstalk between MYC and other oncogenes in programming an immune-suppressive TME.

2.4.3 MYC-Mediated Modulation of Cytokine

MYC-driven tumors exhibit altered cytokine expression that promotes immune evasion. MYC hyperactivation reduces pro-inflammatory cytokines, such as IL-2, interferon-gamma (IFN-\gamma), and perforin, which are critical for effective immune responses. Concurrently, MYC promotes the expression of immunosuppressive cytokines, such as IL-6, further hindering antitumor immunity [16, 86]. In high-grade serous ovarian cancer (HGSC), MYC plays a pivotal role in suppressing cytokine signaling, leading to impaired immune regulation and the creation of immunologically “cold” tumors. MYC represses type I interferon signaling by inhibiting tumor cell-intrinsic innate immune pathways, including STING signaling (via reduced STING oligomerization) and RIG-I-like receptor signaling (by blocking mitochondrial antiviral signaling protein (MAVS) aggregation and mitochondrial localization). This suppression results in decreased expression of chemokines essential for T cell recruitment, thereby reducing TILs in the tumor microenvironment [87]. In NB, MYCN amplification drives an immunologically “cold” TME by suppressing IFN-\gamma signaling and reducing the expression of Th1-type chemokines CXCL9 and CXCL10, which are critical for T cell recruitment. MYCN achieves this by upregulating the activity of epigenetic effectors euchromatic histone-lysine N-methyltransferase 1 (EHMT1) and EHMT2 (G9a), which repress IFN-\gamma transcriptional responses through histone methylation [88]. In innate immune cells, such as NK cells and macrophages, MYC suppresses pro-inflammatory cytokine production, while increasing the secretion of immunosuppressive mediators [89, 90, 91, 92, 93, 94, 95]. MYC dysregulation suppresses NK cell maturation by repressing STAT1/STAT2-dependent Type I interferon signaling, thereby facilitating immune evasion in MYC-driven malignancies [96]. In TAMs, MYC is upregulated in response to signals such as IL-4 and IL-13, driving M2-like macrophage polarization characterized by an anti-inflammatory and pro-tumoral phenotype. Mechanistically, MYC directly controls the expression of genes associated with alternative activation, such as scavenger receptor class B member 1 (SCARB1), arachidonate 15-lipoxygenase (ALOX15), and mannose receptor C-type 1 (MRC1), and indirectly modulates others like CD209 [93]. MYC also upregulates mediators of IL-4 signaling, including STAT6 and peroxisome proliferator activated receptor gamma (PPAR\gamma), further enhancing the M2 profile [97]. This polarization leads to the secretion of immunosuppressive cytokines, such as TGF-\beta, vascular endothelial growth factor (VEGF), and IL-10, which suppress immune responses, promote angiogenesis, and facilitate tumor progression. Conversely, MYC downregulates macrophage colony-stimulating factor 1 (M-CSF) through microRNA regulation, reducing macrophage populations in specific contexts, such as osteosarcoma [67].

Continued research into MYC-driven mechanisms of immune evasion and clinical evaluation of MYC-targeted therapies will be essential for advancing treatment strategies.

2.5 MYC-Mediated T-cell Regulation

MYC is a central regulator of T cell function, dictating metabolic reprogramming, differentiation, and immune checkpoint expression in the tumor microenvironment. Its hyperactivation fuels tumor glycolysis and amino acid consumption, depriving T cells of essential nutrients and driving metabolic exhaustion, impaired proliferation, and diminished effector responses [98]. MYC directly influences T cell fate by controlling amino acid transporter expression, orchestrating metabolic pathways critical for activation and expansion [99]. In highly glycolytic tumors, MYC-driven lactate accumulation enhances PD-1 expression in Tregs, shifting the immune balance toward suppression and undermining immune checkpoint blockade efficacy [100]. Furthermore, MYC upregulates PD-L1 expression in tumors, directly inhibiting T cell activation and promoting immune evasion through PD-1/PD-L1 interactions [101]. By orchestrating both metabolic control and immune suppression, MYC establishes a hostile environment that enforces T cell dysfunction, positioning it as a crucial target for immunotherapeutic strategies aimed at reprogramming T cell responses and enhancing antitumor immunity.

3. Therapeutic Targeting of MYC

Numerous therapeutic strategies have been developed to target MYC and its associated pathways, including both direct inhibition and indirect approaches [102, 103, 104, 105]. Fig. 2 illustrates an overview of strategies for targeting MYC in cancer therapy.

3.1 Direct MYC Inhibition

Direct targeting of MYC focuses on disrupting MYC-MYC-associated factor X (MAX) dimerization using small molecule inhibitors or reducing MYC expression via BET inhibitors. These strategies have shown potential in preclinical models and early clinical trials.

3.1.1 MYC-MAX Dimerization Inhibitors

MYC functions as a transcription factor by forming a heterodimer with MAX, a process essential for its transcriptional activity. Small molecule inhibitors that disrupt this dimerization, such as 10058-F4 and 10074-G5, prevent MYC from binding to E-box sequences in target gene promoters, thereby inhibiting its transcriptional activity and tumor growth [106, 107]. Preclinical models have shown promise for these inhibitors in various MYC-driven cancers. IDP discovery pharma (IDP)-121 is a direct MYC inhibitor designed as a stapled peptide that disrupts MYC-MAX interaction by binding to MYC with high affinity (Kd = 400 nM), preventing its transcriptional activity and demonstrating efficacy in hematologic and solid tumors, making it a promising MYC-targeted therapy currently in clinical trials [108]. WBC100 is a direct MYC degrader that selectively targets the nuclear localization signals (NLS)1-Basic-NLS2 region of MYC, inducing its degradation via the E3 ligase C-terminus of Hsc70-interacting protein (CHIP)-mediated 26S proteasome pathway, leading to apoptosis in MYC-overexpressing cancer cells and demonstrating potent tumor regression in preclinical models [109]. The combination of MYC inhibition by MYCi975 and PD-1 blockade synergistically suppresses tumor progression by remodeling the tumor immune microenvironment [38]. The combination of MYC inhibition and immune checkpoint blockade, specifically anti-PD-L1, significantly enhances tumor regression and extends survival in MYC-driven TNBC. Suppressing MYC increases tumor cell MHC-I expression and immune infiltration, sensitizing tumors to PD-L1 inhibition. Furthermore, the addition of a TLR9 agonist and OX40 agonist to anti-PD-L1 therapy enhances immune activation, leading to complete tumor regression and protection against recurrence, demonstrating a promising strategy to overcome MYC-driven immune evasion [110].

3.1.2 Omomyc Peptide

Omomyc, a dominant-negative mutant of MYC, interferes with MYC-MAX dimerization and blocks its transcriptional activity. This peptide has demonstrated efficacy in various preclinical cancer models and is currently being evaluated in clinical trials [111, 112]. Unlike small molecules, Omomyc directly targets MYC, offering a unique therapeutic approach. Omomyc demonstrated a favorable safety profile, with most adverse effects being mild (Grade 1), primarily low-grade infusion-related reactions commonly observed with biologic therapies. Additionally, the drug exhibited appropriate pharmacokinetic (PK) properties at the recommended dose, with minimal to no signs of immunogenicity [112].

3.2 Indirect Approaches

Indirect approaches to target MYC aim to disrupt MYC-driven processes by inhibiting transcriptional regulators, exploiting synthetic lethality, using dominant-negative peptides, and employing epigenetic modulators.

3.2.1 BET Inhibitors

BET proteins, particularly bromodomain containing protein 4 (BRD4), are key regulators of MYC transcription. BET inhibitors, such as JQ1 and OTX015, competitively bind to bromodomains on BET proteins, displacing BRD4 from chromatin and leading to decreased MYC expression. In preclinical models, BET inhibitors have demonstrated synergy with immune checkpoint inhibitors, enhancing antitumor immune responses [113, 114, 115]. Ongoing clinical trials are evaluating BET inhibitors in hematologic malignancies and solid tumors, with encouraging early-phase results. The combination of BET inhibitors with the BCL-2 antagonist ABT-199 effectively downregulates MYC and CD47 in Lymphoma, reducing cancer cell proliferation and improved treatment outcomes [116].

3.2.2 CDK9 Inhibitors

MYC expression relies on continuous transcription elongation mediated by CDK9, a component of the positive transcription elongation factor b (P-TEFb) complex. CDK9 inhibitors, such as LY2857785, flavopiridol, and dinaciclib, have shown efficacy in reducing MYC expression and inducing apoptosis in MYC-driven tumors [117, 118, 119, 120, 121]. These inhibitors are currently being tested in phase I/II clinical trials, with potential for combination with standard therapies. Enitociclib is an indirect MYC inhibitor that targets CDK9, suppressing RNA polymerase II-mediated transcription, leading to the depletion of MYC and anti-apoptotic myeloid cell leukemia 1 (MCL-1) in MYC+ lymphomas. In preclinical models and patient samples, enitociclib demonstrated tumor growth inhibition, apoptosis activation, and transcriptional downregulation, with clinical activity observed in double-hit diffuse large B-cell lymphoma (DH-DLBCL), highlighting its potential as a novel therapeutic approach for MYC-driven lymphomas [122]. Zotiraciclib (TG02) is an indirect MYC inhibitor that suppresses MYC expression by targeting CDK9, leading to depletion of survival proteins like MYC and MCL-1 in glioblastoma. In a Phase Ib trial (EORTC 1608), TG02 showed dose-dependent toxicity, including neutropenia and hepatotoxicity, with limited single-agent efficacy, highlighting the need for further investigation into CDK9 as a therapeutic target in glioblastoma [123]. KB-0742, a potent CDK9 inhibitor, effectively suppresses MYC protein expression and RNA polymerase II activity, leading to significant anti-tumor effects in MYC-overexpressing TNBC models [124]. KB-0742, shows promising clinical activity in MYC-driven and transcriptionally addicted solid tumors by disrupting MYC-dependent transcription, with manageable toxicity and early signs of durable disease control. Ongoing trials support its use in MYC-overexpressing cancers [125].

3.2.3 Synthetic Lethality Approaches

MYC-driven cancers exhibit specific vulnerabilities, including dependency on certain metabolic pathways and stress response mechanisms. Synthetic lethality-based strategies exploit these vulnerabilities. For example, inhibition of glutaminase (GLS1), an enzyme essential for glutamine metabolism in MYC-overexpressing tumors, creates a metabolic crisis that selectively kills cancer cells [126, 127]. Similarly, targeting DNA damage response pathways with poly ADP-ribose polymerase (PARP) inhibitors in combination with MYC inhibitors has shown promise in preclinical studies [128, 129].

3.2.4 Epigenetic Modulators

MYC is regulated not only by genetic mutations but also through epigenetic changes, which can modulate its expression at both transcriptional and translational levels. Recent studies demonstrate that targeting MYC’s epigenetic modifiers effectively inhibits cancer cell proliferation, sensitizes chemoresistant cells, and improves patient outcomes [130, 131, 132]. Epigenetic therapies targeting MYC, offer promising strategies for improving cancer immunotherapy. The combination of DNA-demethylating agents (DNMTis) and histone deacetylase inhibitors (HDACis) effectively suppresses MYC signaling and enhances immunotherapy in NSCLC. This strategy increases antigen presentation, activates interferon pathways, and elevates the T cell chemoattractant CCL5. In preclinical models, it reverses tumor immune evasion and reprograms T cells into memory and effector states, providing a promising avenue to improve immune checkpoint therapies [66]. OTX-2002 is an indirect MYC inhibitor that functions as an Epigenomic controller (MYC-EC), downregulating MYC expression pre-transcriptionally via targeted DNA methylation modifications, demonstrating durable MYC suppression, tumor inhibition, and manageable safety profiles in early-phase clinical trials [133, 134]. Fimepinostat is an indirect MYC inhibitor that simultaneously targets HDAC and phosphoinositide 3-kinases (PI3K), leading to MYC downregulation and apoptosis in MYC-driven cancers. Preclinical studies demonstrate its efficacy in DH-DLBCL, nuclear protein in testis (NUT) midline carcinoma (NMC), and other MYC-dependent tumors, with significant tumor suppression observed in xenograft and transgenic models, supporting its potential as a targeted therapy for MYC-driven malignancies [135, 136]. The combination of MYC inhibition with HDAC inhibition demonstrates a promising therapeutic strategy for diffuse midline gliomas (DMG) harboring the H3K27M mutation. Sulfopin, a MYC-targeting peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 inhibitor (PIN1) inhibitor, combined with the HDAC inhibitor Vorinostat, significantly reduces tumor cell viability, downregulates oncogenic pathways like mechanistic target of rapamycin (mTOR), and leads to substantial tumor suppression in patient-derived xenograft models. This dual-targeting approach effectively disrupts the epigenetic and transcriptional dysregulation driving DMG, offering a potential treatment avenue for these highly resistant pediatric brain tumors [137].

3.2.5 G-Quadruplex Stabilizers

G-quadruplexes (G4s) are four-stranded DNA structures in guanine-rich regions, including the MYC promoter, where they act as transcriptional silencers [138, 139, 140]. Small molecules that stabilize MYC G4 structures can inhibit MYC transcription, leading to reduced cancer cell proliferation. Compounds like APTO-253 and automated ligand identification system (ALIS)-identified ligands have shown efficacy in downregulating MYC expression, inducing cell cycle arrest and apoptosis, particularly in leukemia models [141, 142]. In a phase I clinical study, APTO-253 demonstrated anti-leukemic activity by selectively reducing MYC mRNA and protein levels through G-quadruplex (G4) stabilization, while inducing p21 expression, cell-cycle arrest, and apoptosis without causing myelosuppression. Its active form, Fe(253)₃, was shown to stabilize G4 structures in MYC and KIT promoters, supporting its targeted mechanism of action [141]. CX-3543 (Quarfloxin), stabilizes G-quadruplex structures in the MYC promoter, leading to transcriptional repression. Similarly, G-quadruplex conformation-05 (GQC-05) (NSC338258) is a potent and selective stabilizer of the MYC G4, reducing MYC transcription by altering protein binding to the nuclease hypersensitive element III (NHE III) (1) promoter region, providing strong evidence for intracellular G4-mediated transcriptional regulation [143].

Despite the intrinsic challenges in directly targeting MYC, recent advances in inhibition strategies—including dimerization disruption, transcriptional repression, and synthetic lethality—have highlighted significant therapeutic potential. Notably, combination approaches that integrate MYC inhibition with immune checkpoint blockade and metabolic modulators have demonstrated promise in overcoming immune evasion and enhancing treatment outcomes in MYC-driven cancers. Preclinical and early clinical studies support the efficacy of these strategies; however, challenges such as tumor heterogeneity, toxicity, and limited response in solid tumors remain. To address these barriers, future research should prioritize patient stratification using immune gene signature sets to better predict responses and guide treatment. Continued exploration of these combination therapies may ultimately expand the therapeutic landscape for patients with MYC-overexpressing malignancies.

3.3 Side Effects of MYC-Targeted Therapies

MYC-targeted therapies present significant challenges due to their widespread effects on normal cellular processes, leading to systemic toxicity, metabolic disruption, immune modulation, and therapy resistance. MYC inhibition impacts rapidly proliferating tissues, particularly in the bone marrow and gastrointestinal epithelium, resulting in myelosuppression, anemia, neutropenia, and gastrointestinal toxicity, as observed in clinical trials of OMO-103 [112]. Additionally, MYC plays a pivotal role in cellular metabolism, and its suppression leads to glucose and glutamine metabolism dysregulation, causing hypoglycemia, oxidative stress, mitochondrial dysfunction, and muscle wasting, significantly affecting energy homeostasis [144]. The immune system is also heavily influenced by MYC inhibition, with studies indicating impaired interferon signaling, PD-L1 upregulation, and disrupted T-cell and NK-cell function, which can paradoxically lead to immune evasion and reduced tumor immunogenicity, thereby limiting the effectiveness of immunotherapies [86]. Another major limitation of MYC-targeted therapies is tumor resistance, as cancer cells can activate alternative oncogenic pathways such as rat sarcoma mitogen activated protein kinase (RAS-MAPK) and PI3K-AKT-mTOR, allowing them to bypass MYC inhibition and sustain growth through metabolic reprogramming [130]. Addressing the off-target effects of MYC-targeted therapies requires a multifaceted approach, combining epigenetic modulation, metabolic inhibitors, synthetic lethality, immune-based strategies, precision drug delivery, and protein interaction disruptors. Clinical trials are actively exploring these methods to improve MYC-targeted therapy while minimizing systemic toxicity, ultimately enhancing the safety and efficacy of these promising treatments.

4. Conclusion and Future Directions

The MYC oncogene plays a central role not only in tumor initiation and progression but also in orchestrating immune evasion within the TIME. MYC-driven tumors employ a range of immunosuppressive strategies, including transcriptional upregulation of immune checkpoints such as PD-L1 and CD47, suppression of antigen presentation machinery (MHC class I and II), modulation of cytokine signaling, and recruitment of immunosuppressive cells such as Tregs and MDSCs. These mechanisms result in impaired T cell activation and infiltration, reduced tumor immunogenicity, and resistance to ICB therapies. Although direct pharmacological inhibition of MYC remains a significant challenge due to its disordered structure and lack of enzymatic activity, several indirect approaches have shown promise. These include CDK9 inhibitors (e.g., KB-0742), which disrupt MYC transcriptional elongation, BET inhibitors (e.g., JQ1), which reduce MYC expression by displacing BRD4 from chromatin, and G-quadruplex stabilizers (e.g., APTO-253), which inhibit MYC transcription by stabilizing secondary DNA structures in its promoter region. These agents not only suppress MYC-driven oncogenic signaling but also contribute to remodeling the TIME by enhancing antigen presentation, restoring interferon signaling, and promoting immune cell infiltration and cytotoxicity. Importantly, combining MYC-targeted therapies with immunotherapies particularly checkpoint inhibitors has demonstrated synergistic anti-tumor effects in preclinical models of MYC-overexpressing cancers such as TNBC, NSCLC, and HCC. Nevertheless, challenges remain, including tumor heterogeneity, compensatory pathway activation, systemic toxicity, and the need for predictive biomarkers to guide patient selection.

Future research should focus on the integration of multi-omics approaches to identify predictive immune-MYC gene signatures, development of rational combination regimens, and implementation of novel delivery platforms to enhance therapeutic specificity. The exploration of rational combination regimens integrating MYC inhibitors with ICB, metabolic inhibitors, epigenetic drugs, or innate immune activators offers a promising path forward. Additionally, advances in drug delivery systems, such as nanoparticle-based carriers, tumor-targeted prodrugs, and proteolysis-targeting chimeras (PROTACs), may enhance specificity and minimize systemic toxicity. Continued investigation into the mechanistic underpinnings of MYC’s influence on the TIME, alongside translational and clinical research, will be critical for unlocking the full therapeutic potential of this approach and improving outcomes for patients with MYC-driven cancers.

References

[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians. 2024; 74: 229–263. https://doi.org/10.3322/caac.21834.

[2] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: a Cancer Journal for Clinicians. 2024; 74: 12–49. https://doi.org/10.3322/caac.21820.

[3] Wu S, Zhu W, Thompson P, Hannun YA. Evaluating intrinsic and non-intrinsic cancer risk factors. Nature Communications. 2018; 9: 3490. https://doi.org/10.1038/s41467-018-05467-z.

[4] Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, et al. High-throughput oncogene mutation profiling in human cancer. Nature Genetics. 2007; 39: 347–351. https://doi.org/10.1038/ng1975.

[5] Mukherjee B, Morgenbesser SD, DePinho RA. Myc family oncoproteins function through a common pathway to transform normal cells in culture: cross-interference by Max and trans-acting dominant mutants. Genes & Development. 1992; 6: 1480–1492. https://doi.org/10.1101/gad.6.8.1480.

[6] Lee M, Seok J, Saha SK, Cho S, Jeong Y, Gil M, et al. Alterations and Co-Occurrence of C-MYC, N-MYC, and L-MYC Expression are Related to Clinical Outcomes in Various Cancers. International Journal of Stem Cells. 2023; 16: 215–233. https://doi.org/10.15283/ijsc22188.

[7] Dang CV. MYC on the path to cancer. Cell. 2012; 149: 22–35. https://doi.org/10.1016/j.cell.2012.03.003.

[8] Schaub FX, Dhankani V, Berger AC, Trivedi M, Richardson AB, Shaw R, et al. Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas. Cell Systems. 2018; 6: 282–300.e2. https://doi.org/10.1016/j.cels.2018.03.003.

[9] Sias F, Zoroddu S, Migheli R, Bagella L. Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target. International Journal of Molecular Sciences. 2025; 26: 1973. https://doi.org/10.3390/ijms26051973.

[10] Olsen RR, Otero JH, García-López J, Wallace K, Finkelstein D, Rehg JE, et al. MYCN induces neuroblastoma in primary neural crest cells. Oncogene. 2017; 36: 5075–5082. https://doi.org/10.1038/onc.2017.128.

[11] Duffy MJ, O’Grady S, Tang M, Crown J. MYC as a target for cancer treatment. Cancer Treatment Reviews. 2021; 94: 102154. https://doi.org/10.1016/j.ctrv.2021.102154.

[12] Ahmadi SE, Rahimi S, Zarandi B, Chegeni R, Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. Journal of Hematology & Oncology. 2021; 14: 121. https://doi.org/10.1186/s13045-021-01111-4.

[13] Jha RK, Kouzine F, Levens D. MYC function and regulation in physiological perspective. Frontiers in Cell and Developmental Biology. 2023; 11: 1268275. https://doi.org/10.3389/fcell.2023.1268275.

[14] Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, Metabolism, and Cancer. Cancer Discovery. 2015; 5: 1024–1039. https://doi.org/10.1158/2159-8290.CD-15-0507.

[15] Meškytė EM, Keskas S, Ciribilli Y. MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis. International Journal of Molecular Sciences. 2020; 21: 7710. https://doi.org/10.3390/ijms21207710.

[16] Li J, Dong T, Wu Z, Zhu D, Gu H. The effects of MYC on tumor immunity and immunotherapy. Cell Death Discovery. 2023; 9: 103. https://doi.org/10.1038/s41420-023-01403-3.

[17] Casey SC, Baylot V, Felsher DW. The MYC oncogene is a global regulator of the immune response. Blood. 2018; 131: 2007–2015. https://doi.org/10.1182/blood-2017-11-742577.

[18] Wu X, Nelson M, Basu M, Srinivasan P, Lazarski C, Zhang P, et al. MYC oncogene is associated with suppression of tumor immunity and targeting Myc induces tumor cell immunogenicity for therapeutic whole cell vaccination. Journal for Immunotherapy of Cancer. 2021; 9: e001388. https://doi.org/10.1136/jitc-2020-001388.

[19] de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023; 41: 374–403. https://doi.org/10.1016/j.ccell.2023.02.016.

[20] Anderson NM, Simon MC. The tumor microenvironment. Current Biology: CB. 2020; 30: R921–R925. https://doi.org/10.1016/j.cub.2020.06.081.

[21] Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Communication and Signaling: CCS. 2020; 18: 59. https://doi.org/10.1186/s12964-020-0530-4.

[22] Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012; 21: 309–322. https://doi.org/10.1016/j.ccr.2012.02.022.

[23] Nirala BK, Yamamichi T, Petrescu DI, Shafin TN, Yustein JT. Decoding the Impact of Tumor Microenvironment in Osteosarcoma Progression and Metastasis. Cancers. 2023; 15: 5108. https://doi.org/10.3390/cancers15205108.

[24] Krenz B, Lee J, Kannan T, Eilers M. Immune evasion: An imperative and consequence of MYC deregulation. Molecular Oncology. 2024; 18: 2338–2355. https://doi.org/10.1002/1878-0261.13695.

[25] Cyberski TF, Singh A, Korzinkin M, Mishra V, Pun F, Shen L, et al. Acquired resistance to immunotherapy and chemoradiation in MYC amplified head and neck cancer. NPJ Precision Oncology. 2024; 8: 114. https://doi.org/10.1038/s41698-024-00606-w.

[26] Donati G, Amati B. MYC and therapy resistance in cancer: risks and opportunities. Molecular Oncology. 2022; 16: 3828–3854. https://doi.org/10.1002/1878-0261.13319.

[27] Wojtukiewicz MZ, Rek MM, Karpowicz K, Górska M, Polityńska B, Wojtukiewicz AM, et al. Inhibitors of immune checkpoints-PD-1, PD-L1, CTLA-4-new opportunities for cancer patients and a new challenge for internists and general practitioners. Cancer Metastasis Reviews. 2021; 40: 949–982. https://doi.org/10.1007/s10555-021-09976-0.

[28] Javed SA, Najmi A, Ahsan W, Zoghebi K. Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges. Frontiers in Immunology. 2024; 15: 1383456. https://doi.org/10.3389/fimmu.2024.1383456.

[29] Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduction and Targeted Therapy. 2023; 8: 320. https://doi.org/10.1038/s41392-023-01522-4.

[30] Cheng W, Kang K, Zhao A, Wu Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. Journal of Hematology & Oncology. 2024; 17: 54. https://doi.org/10.1186/s13045-024-01581-2.

[31] Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2015; 33: 1974–1982. https://doi.org/10.1200/JCO.2014.59.4358.

[32] Huang AC, Zappasodi R. A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nature Immunology. 2022; 23: 660–670. https://doi.org/10.1038/s41590-022-01141-1.

[33] Lauss M, Phung B, Borch TH, Harbst K, Kaminska K, Ebbesson A, et al. Molecular patterns of resistance to immune checkpoint blockade in melanoma. Nature Communications. 2024; 15: 3075. https://doi.org/10.1038/s41467-024-47425-y.

[34] Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discovery. 2018; 8: 1069–1086. https://doi.org/10.1158/2159-8290.CD-18-0367.

[35] Sharma P, Goswami S, Raychaudhuri D, Siddiqui BA, Singh P, Nagarajan A, et al. Immune checkpoint therapy-current perspectives and future directions. Cell. 2023; 186: 1652–1669. https://doi.org/10.1016/j.cell.2023.03.006.

[36] Markovits E, Harush O, Baruch EN, Shulman ED, Debby A, Itzhaki O, et al. MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2. Cancer Immunology Research. 2023; 11: 909–924. https://doi.org/10.1158/2326-6066.CIR-22-0184.

[37] Kim EY, Kim A, Kim SK, Chang YS. MYC expression correlates with PD-L1 expression in non-small cell lung cancer. Lung Cancer (Amsterdam, Netherlands). 2017; 110: 63–67. https://doi.org/10.1016/j.lungcan.2017.06.006.

[38] Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, et al. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell. 2019; 36: 483–497.e15. https://doi.org/10.1016/j.ccell.2019.10.001.

[39] Yang A, Qin S, Schulte BA, Ethier SP, Tew KD, Wang GY. MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer. Cancer Research. 2017; 77: 6641–6650. https://doi.org/10.1158/0008-5472.CAN-16-3452.

[40] Massó-Vallés D, Beaulieu ME, Jauset T, Giuntini F, Zacarías-Fluck MF, Foradada L, et al. MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding. Cancer Research Communications. 2022; 2: 110–130. https://doi.org/10.1158/2767-9764.CRC-21-0103.

[41] Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, et al. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget. 2016; 7: 31014–31028. https://doi.org/10.18632/oncotarget.8826.

[42] Bouvard C, Lim SM, Ludka J, Yazdani N, Woods AK, Chatterjee AK, et al. Small molecule selectively suppresses MYC transcription in cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2017; 114: 3497–3502. https://doi.org/10.1073/pnas.1702663114.

[43] Carabet LA, Rennie PS, Cherkasov A. Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches. International Journal of Molecular Sciences. 2018; 20: 120. https://doi.org/10.3390/ijms20010120.

[44] Wu SY, Xiao Y, Wei JL, Xu XE, Jin X, Hu X, et al. MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer. Journal for Immunotherapy of Cancer. 2021; 9: e002528. https://doi.org/10.1136/jitc-2021-002528.

[45] Jiang K, Zhang Q, Fan Y, Li J, Zhang J, Wang W, et al. MYC inhibition reprograms tumor immune microenvironment by recruiting T lymphocytes and activating the CD40/CD40L system in osteosarcoma. Cell Death Discovery. 2022; 8: 117. https://doi.org/10.1038/s41420-022-00923-8.

[46] Liu X, Liu L, Ren Z, Yang K, Xu H, Luan Y, et al. Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion. Cell Reports. 2018; 24: 2101–2111. https://doi.org/10.1016/j.celrep.2018.07.062.

[47] Dhanasekaran R, Hansen AS, Park J, Lemaitre L, Lai I, Adeniji N, et al. MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages. Cancer Research. 2023; 83: 626–640. https://doi.org/10.1158/0008-5472.CAN-22-0232.

[48] Liang MQ, Yu FQ, Chen C. C-Myc regulates PD-L1 expression in esophageal squamous cell carcinoma. American Journal of Translational Research. 2020; 12: 379–388.

[49] Zhang F, Hu K, Liu W, Quan B, Li M, Lu S, et al. Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment. Cellular and Molecular Gastroenterology and Hepatology. 2023; 15: 573–591. https://doi.org/10.1016/j.jcmgh.2022.12.002.

[50] Wang J, Yang Y, Shao F, Meng Y, Guo D, He J, et al. Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc. Nature Metabolism. 2024; 6: 914–932. https://doi.org/10.1038/s42255-024-01037-4.

[51] Pan Y, Fei Q, Xiong P, Yang J, Zhang Z, Lin X, et al. Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1. Oncoimmunology. 2019; 8: e1581529. https://doi.org/10.1080/2162402X.2019.1581529.

[52] Zhao PY, Sun XD, Li H, Tian L, Lu YH, Cheng Y. The effect of c-Myc on regulating the immune-related ligands in Y subtype small cell lung cancer through histone deacetylase 1. Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology]. 2024; 46: 1009–1018. https://doi.org/10.3760/cma.j.cn112152-20230803-00058. (In Chinese)

[53] Liu L, Gong D, Sun H, Feng F, Xu J, Sun X, et al. DNp73 enhances tumor progression and immune evasion in multiple myeloma by targeting the MYC and MYCN pathways. Frontiers in Immunology. 2024; 15: 1470328. https://doi.org/10.3389/fimmu.2024.1470328.

[54] Hashimoto A, Handa H, Hata S, Tsutaho A, Yoshida T, Hirano S, et al. Inhibition of mutant KRAS-driven overexpression of ARF6 and MYC by an eIF4A inhibitor drug improves the effects of anti-PD-1 immunotherapy for pancreatic cancer. Cell Communication and Signaling: CCS. 2021; 19: 54. https://doi.org/10.1186/s12964-021-00733-y.

[55] Nardi F, Perurena N, Schade AE, Li ZH, Ngo K, Ivanova EV, et al. Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer. The Journal of Clinical Investigation. 2023; 133: e167651. https://doi.org/10.1172/JCI167651.

[56] Lee JV, Housley F, Yau C, Nakagawa R, Winkler J, Anttila JM, et al. Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer. Nature Communications. 2022; 13: 3671. https://doi.org/10.1038/s41467-022-31238-y.

[57] God JM, Cameron C, Figueroa J, Amria S, Hossain A, Kempkes B, et al. Elevation of c-MYC disrupts HLA class II-mediated immune recognition of human B cell tumors. Journal of Immunology (Baltimore, Md.: 1950). 2015; 194: 1434–1445. https://doi.org/10.4049/jimmunol.1402382.

[58] Versteeg R, Noordermeer IA, Krüse-Wolters M, Ruiter DJ, Schrier PI. c-myc down-regulates class I HLA expression in human melanomas. The EMBO Journal. 1988; 7: 1023–1029. https://doi.org/10.1002/j.1460-2075.1988.tb02909.x.

[59] Bernards R, Dessain SK, Weinberg RA. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell. 1986; 47: 667–674. https://doi.org/10.1016/0092-8674(86)90509-x.

[60] Jia X, Yan B, Tian X, Liu Q, Jin J, Shi J, et al. CD47/SIRPα pathway mediates cancer immune escape and immunotherapy. International Journal of Biological Sciences. 2021; 17: 3281–3287. https://doi.org/10.7150/ijbs.60782.

[61] van’t Veer LJ, Beijersbergen RL, Bernards R. N-myc suppresses major histocompatibility complex class I gene expression through down-regulation of the p50 subunit of NF-kappa B. The EMBO Journal. 1993; 12: 195–200. https://doi.org/10.1002/j.1460-2075.1993.tb05645.x.

[62] Cheng NC, Beitsma M, Chan A, Op den Camp I, Westerveld A, Pronk J, et al. Lack of class I HLA expression in neuroblastoma is associated with high N-myc expression and hypomethylation due to loss of the MEMO-1 locus. Oncogene. 1996; 13: 1737–1744.

[63] Tudor CS, Dawson CW, Eckhardt J, Niedobitek G, Büttner AC, Seliger B, et al. c-Myc and EBV-LMP1: two opposing regulators of the HLA class I antigen presentation machinery in epithelial cells. British Journal of Cancer. 2012; 106: 1980–1988. https://doi.org/10.1038/bjc.2012.197.

[64] Demel UM, Böger M, Yousefian S, Grunert C, Zhang L, Hotz PW, et al. Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer. The Journal of Clinical Investigation. 2022; 132: e152383. https://doi.org/10.1172/JCI152383.

[65] Yazawa T, Ito T, Kamma H, Suzuki T, Okudela K, Hayashi H, et al. Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma. The American Journal of Pathology. 2002; 161: 291–300. https://doi.org/10.1016/S0002-9440(10)64181-8.

[66] Topper MJ, Vaz M, Chiappinelli KB, DeStefano Shields CE, Niknafs N, Yen RWC, et al. Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell. 2017; 171: 1284–1300.e21. https://doi.org/10.1016/j.cell.2017.10.022.

[67] Nirala BK, Patel TD, Kurenbekova L, Shuck R, Dasgupta A, Rainusso N, et al. MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma. JCI Insight. 2023; 8: e164947. https://doi.org/10.1172/jci.insight.164947.

[68] Yuen VWH, Chiu DKC, Law CT, Cheu JWS, Chan CYK, Wong BPY, et al. Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses. Journal of Hepatology. 2023; 78: 376–389. https://doi.org/10.1016/j.jhep.2022.10.037.

[69] Kortlever RM, Sodir NM, Wilson CH, Burkhart DL, Pellegrinet L, Brown Swigart L, et al. Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell. 2017; 171: 1301–1315.e14. https://doi.org/10.1016/j.cell.2017.11.013.

[70] Pello OM, Andrés V. Role of c-MYC in tumor-associated macrophages and cancer progression. Oncoimmunology. 2013; 2: e22984. https://doi.org/10.4161/onci.22984.

[71] Gao FY, Li XT, Xu K, Wang RT, Guan XX. c-MYC mediates the crosstalk between breast cancer cells and tumor microenvironment. Cell Communication and Signaling: CCS. 2023; 21: 28. https://doi.org/10.1186/s12964-023-01043-1.

[72] Ischenko I, D’Amico S, Rao M, Li J, Hayman MJ, Powers S, et al. KRAS drives immune evasion in a genetic model of pancreatic cancer. Nature Communications. 2021; 12: 1482. https://doi.org/10.1038/s41467-021-21736-w.

[73] Jin Y, Qiu J, Lu X, Li G. C-MYC Inhibited Ferroptosis and Promoted Immune Evasion in Ovarian Cancer Cells through NCOA4 Mediated Ferritin Autophagy. Cells. 2022; 11: 4127. https://doi.org/10.3390/cells11244127.

[74] Nirala BK, Yamamichi T, Yustein JT. Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis. International Journal of Molecular Sciences. 2023; 24: 11367. https://doi.org/10.3390/ijms241411367.

[75] Sabe H. KRAS, MYC, and ARF6: inseparable relationships cooperatively promote cancer malignancy and immune evasion. Cell Communication and Signaling: CCS. 2023; 21: 106. https://doi.org/10.1186/s12964-023-01130-3.

[76] Casacuberta-Serra S, González-Larreategui Í Capitán-Leo D, Soucek L. MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer. Signal Transduction and Targeted Therapy. 2024; 9: 205. https://doi.org/10.1038/s41392-024-01907-z.

[77] Kortlever RM, Sodir NM, Wilson CH, Burkhart DL, Pellegrinet L, Brown Swigart L, et al. MYC Induces Immune Suppression to Promote Lung Tumorigenesis. Cancer Discovery. 2018; 8: 13. https://doi.org/10.1158/2159-8290.Cd-rw2017-232.

[78] Vaseva AV, Blake DR, Gilbert TSK, Ng S, Hostetter G, Azam SH, et al. KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell. 2018; 34: 807–822.e7. https://doi.org/10.1016/j.ccell.2018.10.001.

[79] Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017; 8: 33972–33989. https://doi.org/10.18632/oncotarget.15687.

[80] Rennoll S, Yochum G. Regulation of MYC gene expression by aberrant Wnt/β-catenin signaling in colorectal cancer. World Journal of Biological Chemistry. 2015; 6: 290–300. https://doi.org/10.4331/wjbc.v6.i4.290.

[81] Gao X, You J, Gong Y, Yuan M, Zhu H, Fang L, et al. WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit. Acta Pharmaceutica Sinica. B. 2022; 12: 1225–1239. https://doi.org/10.1016/j.apsb.2021.10.021.

[82] Calvisi DF, Ladu S, Factor VM, Thorgeirsson SS. Activation of beta-catenin provides proliferative and invasive advantages in c-myc/TGF-alpha hepatocarcinogenesis promoted by phenobarbital. Carcinogenesis. 2004; 25: 901–908. https://doi.org/10.1093/carcin/bgh083.

[83] Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, et al. β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discovery. 2019; 9: 1124–1141. https://doi.org/10.1158/2159-8290.CD-19-0074.

[84] Yang X, Shao F, Guo D, Wang W, Wang J, Zhu R, et al. WNT/β-catenin-suppressed FTO expression increases m⁶A of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis. Cell Death & Disease. 2021; 12: 462. https://doi.org/10.1038/s41419-021-03739-z.

[85] Madapura HS, Salamon D, Wiman KG, Lain S, Klein E, Nagy N. cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response. Cell Cycle (Georgetown, Tex.). 2016; 15: 1267–1275. https://doi.org/10.1080/15384101.2016.1160975.

[86] Alburquerque-Bejar JJ, Navajas-Chocarro P, Saigi M, Ferrero-Andres A, Morillas JM, Vilarrubi A, et al. MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer. Cell Reports. Medicine. 2023; 4: 101006. https://doi.org/10.1016/j.xcrm.2023.101006.

[87] Miranda A, Pattnaik S, Hamilton PT, Fuss MA, Kalaria S, Laumont CM, et al. N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma. Science Advances. 2024; 10: eadj5428. https://doi.org/10.1126/sciadv.adj5428.

[88] Seier JA, Reinhardt J, Saraf K, Ng SS, Layer JP, Corvino D, et al. Druggable epigenetic suppression of interferon-induced chemokine expression linked to MYCN amplification in neuroblastoma. Journal for Immunotherapy of Cancer. 2021; 9: e001335. https://doi.org/10.1136/jitc-2020-001335.

[89] Swaminathan S, Hansen AS, Heftdal LD, Dhanasekaran R, Deutzmann A, Fernandez WDM, et al. MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies. Nature Communications. 2020; 11: 2860. https://doi.org/10.1038/s41467-020-16447-7.

[90] Khameneh HJ, Fonta N, Zenobi A, Niogret C, Ventura P, Guerra C, et al. Myc controls NK cell development, IL-15-driven expansion, and translational machinery. Life Science Alliance. 2023; 6. https://doi.org/10.26508/lsa.202302069.

[91] Lee YS, Heo W, Son CH, Kang CD, Park YS, Bae J. Upregulation of Myc promotes the evasion of NK cell mediated immunity through suppression of NKG2D ligands in K562 cells. Molecular Medicine Reports. 2019; 20: 3301–3307. https://doi.org/10.3892/mmr.2019.10583.

[92] Tang Y, Yan X, Zhan D, Wen L, Huang R, Zhang Y, et al. Myc Regulates the Development and Anti-Tumor Immunity of Natural Killer Cells. Blood. 2018; 132: 1113. https://doi.org/10.1182/blood-2018-99-114180.

[93] Pello OM, De Pizzol M, Mirolo M, Soucek L, Zammataro L, Amabile A, et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood. 2012; 119: 411–421. https://doi.org/10.1182/blood-2011-02-339911.

[94] Bae S, Park PSU, Lee Y, Mun SH, Giannopoulou E, Fujii T, et al. MYC-mediated early glycolysis negatively regulates proinflammatory responses by controlling IRF4 in inflammatory macrophages. Cell Reports. 2021; 35: 109264. https://doi.org/10.1016/j.celrep.2021.109264.

[95] Pello OM. Macrophages and c-Myc cross paths. Oncoimmunology. 2016; 5: e1151991. https://doi.org/10.1080/2162402X.2016.1151991.

[96] Muthalagu N, Monteverde T, Raffo-Iraolagoitia X, Wiesheu R, Whyte D, Hedley A, et al. Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma. Cancer Discovery. 2020; 10: 872–887. https://doi.org/10.1158/2159-8290.CD-19-0620.

[97] Luiz JPM, Toller-Kawahisa JE, Viacava PR, Nascimento DC, Pereira PT, Saraiva AL, et al. MEK5/ERK5 signaling mediates IL-4-induced M2 macrophage differentiation through regulation of c-Myc expression. Journal of Leukocyte Biology. 2020; 108: 1215–1223. https://doi.org/10.1002/JLB.1MA0520-016R.

[98] Feng B, Li R, Li W, Tang L. Metabolic immunoengineering approaches to enhance CD8⁺ T cell-based cancer immunotherapy. Cell Systems. 2024; 15: 1225–1244. https://doi.org/10.1016/j.cels.2024.11.010.

[99] Marchingo JM, Sinclair LV, Howden AJ, Cantrell DA. Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation. eLife. 2020; 9: e53725. https://doi.org/10.7554/eLife.53725.

[100] Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022; 40: 201–218.e9. https://doi.org/10.1016/j.ccell.2022.01.001.

[101] Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011; 35: 871–882. https://doi.org/10.1016/j.immuni.2011.09.021.

[102] Xie X, Yu T, Li X, Zhang N, Foster LJ, Peng C, et al. Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials. Signal Transduction and Targeted Therapy. 2023; 8: 335. https://doi.org/10.1038/s41392-023-01589-z.

[103] Ting TA, Chaumet A, Bard FA. Targeting c-Myc with a novel Peptide Nuclear Delivery Device. Scientific Reports. 2020; 10: 17762. https://doi.org/10.1038/s41598-020-73998-x.

[104] Llombart V, Mansour MR. Therapeutic targeting of “undruggable” MYC. EBioMedicine. 2022; 75: 103756. https://doi.org/10.1016/j.ebiom.2021.103756.

[105] Wang C, Zhang J, Yin J, Gan Y, Xu S, Gu Y, et al. Alternative approaches to target Myc for cancer treatment. Signal Transduction and Targeted Therapy. 2021; 6: 117. https://doi.org/10.1038/s41392-021-00500-y.

[106] Yin X, Giap C, Lazo JS, Prochownik EV. Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene. 2003; 22: 6151–6159. https://doi.org/10.1038/sj.onc.1206641.

[107] Müller I, Larsson K, Frenzel A, Oliynyk G, Zirath H, Prochownik EV, et al. Targeting of the MYCN protein with small molecule c-MYC inhibitors. PloS One. 2014; 9: e97285. https://doi.org/10.1371/journal.pone.0097285.

[108] Calvis C, Beier A, Feichtinger M, Höfurthner T, Moreno M, Messeguer R, et al. Abstract 2471: IDP-121, a first in class staple peptide targeting c-MYC. Cancer Research. 2021; 81: 2471. https://doi.org/10.1158/1538-7445.Am2021-2471.

[109] Xu Y, Yu Q, Wang P, Wu Z, Zhang L, Wu S, et al. A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2022; 9: e2104344. https://doi.org/10.1002/advs.202104344.

[110] Lee JV, Housley F, Yau C, Van de Mark D, Nakagawa R, Hemmati G, et al. Combinatorial Immunotherapies Overcome MYC-Driven Immune Evasion. bioRxiv. 2021. https://doi.org/10.1101/2021.05.07.442684. (preprint)

[111] Soucek L, Whitfield JR, Sodir NM, Massó-Vallés D, Serrano E, Karnezis AN, et al. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes & Development. 2013; 27: 504–513. https://doi.org/10.1101/gad.205542.112.

[112] Garralda E, Beaulieu ME, Moreno V, Casacuberta-Serra S, Martínez-Martín S, Foradada L, et al. MYC targeting by OMO-103 in solid tumors: a phase 1 trial. Nature Medicine. 2024; 30: 762–771. https://doi.org/10.1038/s41591-024-02805-1.

[113] Ott CJ, Kopp N, Bird L, Paranal RM, Qi J, Bowman T, et al. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012; 120: 2843–2852. https://doi.org/10.1182/blood-2012-02-413021.

[114] Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146: 904–917. https://doi.org/10.1016/j.cell.2011.08.017.

[115] Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108: 16669–16674. https://doi.org/10.1073/pnas.1108190108.

[116] Li W, Gupta SK, Han W, Kundson RA, Nelson S, Knutson D, et al. Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors. Journal of Hematology & Oncology. 2019; 12: 73. https://doi.org/10.1186/s13045-019-0761-2.

[117] Huang CH, Lujambio A, Zuber J, Tschaharganeh DF, Doran MG, Evans MJ, et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes & Development. 2014; 28: 1800–1814. https://doi.org/10.1101/gad.244368.114.

[118] Phillips DC, Jin S, Gregory GP, Zhang Q, Xue J, Zhao X, et al. A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies. Leukemia. 2020; 34: 1646–1657. https://doi.org/10.1038/s41375-019-0652-0.

[119] Yin T, Lallena MJ, Kreklau EL, Fales KR, Carballares S, Torrres R, et al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Molecular Cancer Therapeutics. 2014; 13: 1442–1456. https://doi.org/10.1158/1535-7163.MCT-13-0849.

[120] Boffo S, Damato A, Alfano L, Giordano A. CDK9 inhibitors in acute myeloid leukemia. Journal of Experimental & Clinical Cancer Research: CR. 2018; 37: 36. https://doi.org/10.1186/s13046-018-0704-8.

[121] Mo C, Wei N, Li T, Ahmed Bhat M, Mohammadi M, Kuang C. CDK9 inhibitors for the treatment of solid tumors. Biochemical Pharmacology. 2024; 229: 116470. https://doi.org/10.1016/j.bcp.2024.116470.

[122] Frigault MM, Mithal A, Wong H, Stelte-Ludwig B, Mandava V, Huang X, et al. Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription. Cancer Research Communications. 2023; 3: 2268–2279. https://doi.org/10.1158/2767-9764.CRC-23-0219.

[123] Le Rhun E, Gorlia T, Felsberg J, Jongen J, Maurage CA, Ducray F, et al. Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial. European Journal of Cancer (Oxford, England: 1990). 2024; 198: 113475. https://doi.org/10.1016/j.ejca.2023.113475.

[124] Saffran DC, Day MA, Rioux N, Chen T, Lee C, Amara SN-A, et al. Abstract P5-08-05: Preclinical activity of KB-0742, an oral, highly selective, CDK9 inhibitor, in cell lines and in MYC-high expressing, patient-derived models of multiple breast cancer subtypes. Cancer Research. 2022; 82: P5-08-05. https://doi.org/10.1158/1538-7445.SABCS21-P5-08-05.

[125] Villalona-Calero MA, Hanna GJ, Agulnik M, Mita MM, Mita AC, Spigel DR, et al. Study update of the oral CDK9 inhibitor KB-0742 in relapsed or refractory transcriptionally addicted advanced solid tumors. Journal of Clinical Oncology. 2024; 42: 3102. https://doi.org/10.1200/JCO.2024.42.16_suppl.3102.

[126] Cermelli S, Jang IS, Bernard B, Grandori C. Synthetic lethal screens as a means to understand and treat MYC-driven cancers. Cold Spring Harbor Perspectives in Medicine. 2014; 4. https://doi.org/10.1101/cshperspect.a014209.

[127] Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism. 2012; 15: 110–121. https://doi.org/10.1016/j.cmet.2011.12.009.

[128] Carey JPW, Karakas C, Bui T, Chen X, Vijayaraghavan S, Zhao Y, et al. Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer. Cancer Research. 2018; 78: 742–757. https://doi.org/10.1158/0008-5472.CAN-17-1494.

[129] Konecny GE. Combining PARP and CDK4/6 inhibitors in MYC driven ovarian cancer. EBioMedicine. 2019; 43: 9–10. https://doi.org/10.1016/j.ebiom.2019.04.009.

[130] Senapedis W, Gallagher KM, Figueroa E, Farelli JD, Lyng R, Hodgson JG, et al. Targeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models. Nature Communications. 2024; 15: 7875. https://doi.org/10.1038/s41467-024-52202-y.

[131] Yang Z, Shah K, Busby T, Giles K, Khodadadi-Jamayran A, Li W, et al. Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer. The Journal of Clinical Investigation. 2018; 128: 3605–3618. https://doi.org/10.1172/JCI97072.

[132] Amjadi-Moheb F, Paniri A, Akhavan-Niaki H. Insights into the Links between MYC and 3D Chromatin Structure and Epigenetics Regulation: Implications for Cancer Therapy. Cancer Research. 2021; 81: 1925–1936. https://doi.org/10.1158/0008-5472.CAN-20-3613.

[133] Mizrahi J, Senapedis W, O’Donnell C, Hodgson JG, Newman JV, Siecinski SK, Lin CC. First-in-human phase 1/2 study (MYCHELANGELO I) of first-in-class epigenomic controller OTX-2002 targeting MYC oncogene in patients with hepatocellular carcinoma (HCC) and other solid tumors. Journal of Clinical Oncology. 2025; 43: 606. https://doi.org/10.1200/JCO.2025.43.4_suppl.606.

[134] Rodriguez-Rivera II, Wu TH, Ciotti R, Senapedis W, Sullivan K, Gao JZ, et al. A phase 1/2 open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of OTX-2002 as a single agent and in combination with standard of care in patients with hepatocellular carcinoma and other solid tumor types known for association with the MYC oncogene (MYCHELANGELO I). Journal of Clinical Oncology. 2023; 41: TPS627. https://doi.org/10.1200/JCO.2023.41.4_suppl.TPS627.

[135] Sun K, Atoyan R, Borek MA, Dellarocca S, Samson MES, Ma AW, et al. Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers. Molecular Cancer Therapeutics. 2017; 16: 285–299. https://doi.org/10.1158/1535-7163.MCT-16-0390.

[136] Landsburg DJ, Ramchandren R, Oki Y, Pagel JM, Lugtenburg PJ, Gharavi R, et al. Objective Responses Achieved in Patients with MYC-Altered Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with the Dual PI3K and HDAC Inhibitor CUDC-907. Blood. 2017; 130: 1555. https://doi.org/10.1182/blood.V130.Suppl_1.1555.1555.

[137] Algranati D, Oren R, Dassa B, Fellus-Alyagor L, Plotnikov A, Barr H, et al. Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas. eLife. 2024; 13. https://doi.org/10.7554/eLife.96257.

[138] Esain-Garcia I, Kirchner A, Melidis L, Tavares RDCA, Dhir S, Simeone A, et al. G-quadruplex DNA structure is a positive regulator of MYC transcription. Proceedings of the National Academy of Sciences of the United States of America. 2024; 121: e2320240121. https://doi.org/10.1073/pnas.2320240121.

[139] Wang W, Hu S, Gu Y, Yan Y, Stovall DB, Li D, et al. Human MYC G-quadruplex: From discovery to a cancer therapeutic target. Biochimica et Biophysica Acta. Reviews on Cancer. 2020; 1874: 188410. https://doi.org/10.1016/j.bbcan.2020.188410.

[140] Asamitsu S, Obata S, Yu Z, Bando T, Sugiyama H. Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy. Molecules (Basel, Switzerland). 2019; 24: 429. https://doi.org/10.3390/molecules24030429.

[141] Local A, Zhang H, Benbatoul KD, Folger P, Sheng X, Tsai CY, et al. APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells. Molecular Cancer Therapeutics. 2018; 17: 1177–1186. https://doi.org/10.1158/1535-7163.MCT-17-1209.

[142] Flusberg DA, Rizvi NF, Kutilek V, Andrews C, Saradjian P, Chamberlin C, et al. Identification of G-Quadruplex-Binding Inhibitors of Myc Expression through Affinity Selection-Mass Spectrometry. SLAS Discovery: Advancing Life Sciences R & D. 2019; 24: 142–157. https://doi.org/10.1177/2472555218796656.

[143] Brown RV, Danford FL, Gokhale V, Hurley LH, Brooks TA. Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex. The Journal of Biological Chemistry. 2011; 286: 41018–41027. https://doi.org/10.1074/jbc.M111.274720.

[144] D’Avola A, Kluckova K, Finch AJ, Riches JC. Spotlight on New Therapeutic Opportunities for MYC-Driven Cancers. OncoTargets and Therapy. 2023; 16: 371–383. https://doi.org/10.2147/OTT.S366627.

Funding

National Institute of Health(1R01EB026453)

National Institute of Health(1R01CA21554)

National Institute of Health(1R21CA267914)

Osteosarcoma Institute