Next Article in Journal
Lurasidone for Pediatric Bipolar Disorder: A Systematic Review
Previous Article in Journal
Study on the Pharmacological Efficacy and Mechanism of Dual-Target Liposome Complex AD808 Against Alzheimer’s Disease
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 18
Issue 7
10.3390/ph18070978
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Beyond the Limit: MYC Mediates Tumor Immune Escape

by
Zhongyang Hong
1,†,
Sitong Ming
1,†,
Xin Luan
2,
Zhe Sun
2,* and
Weidong Zhang
3,4,*
1
School of Pharmaceutical Science, Changchun University of Chinese Medicine, Changchun 130117, China
2
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China
3
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
4
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceuticals 2025, 18(7), 978; https://doi.org/10.3390/ph18070978
Submission received: 27 May 2025 / Revised: 22 June 2025 / Accepted: 24 June 2025 / Published: 29 June 2025
(This article belongs to the Section Biopharmaceuticals)
Browse Figures
Versions Notes

Abstract

MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, a phenomenon referred to as oncogene addiction. However, in vitro studies reveal that the knockout or knockdown of MYC in numerous tumor cell lines does not necessarily result in cell death, despite these tumors exhibiting MYC addiction in vivo. This discrepancy suggests that the unique tumor microenvironment in vivo may play a critical role in facilitating MYC addiction in cancer cells. MYC is also widely acknowledged for its role in mediating the immune evasion of tumor cells. Nevertheless, due to the extensive regulation of cellular gene expression by MYC and the incomplete understanding of the mechanisms underlying tumor immune escape, the precise pathways through which MYC influences tumor immune evasion remain inadequately elucidated. Recent years have seen the identification of novel tumor immune escape mechanisms, some of which have been demonstrated to be directly or indirectly regulated by MYC. For instance, MYC may contribute to immune evasion by modulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine biosynthesis. Herein, in this study, we explore some novel potential mechanisms through which MYC facilitates the immune evasion of tumor cells, alongside a combined therapeutic approach targeting MYC and employing immunotherapy based on this mechanism. Furthermore, we suggest that targeting proteins interacting with MYC to modulate its expression and function may serve as an alternative strategy to direct MYC targeting, thereby expediting the clinical translation of combination therapies.

1. MYC

The oncoprotein MYC is a master regulator of a diverse set of biological programmes and a transcription factor that regulates the expression of thousands of genes, either directly or indirectly [1,2]. These genes influence both cell-intrinsic biology and host immunity and the tumor microenvironment (TME) [3,4,5,6,7,8]. The MYC family comprises three oncogenes, namely, MYC, MYCN, and MYCL (Figure 1). Among them, MYC is the most widely expressed, covering almost all cancers, whereas MYCN and MYCL are expressed mainly in neuroblastoma and small cell lung cancer, respectively. Importantly, recent studies have shown that MYCN and MYCL are also expressed in other cancers, driving tumor development [9,10,11,12,13,14,15].
In healthy cells, MYC is rigorously regulated to ensure that the diverse biological functions it governs are executed in a precise and coordinated manner. However, in approximately 70% of cancer cases, MYC is dysregulated, which is characterized by markedly elevated expression levels and excessive activation of its transcriptional function, enabling tumor cells to proliferate uncontrollably and potentially metastasize to nonprimary tissues. Moreover, the activation of MYC resulted in the development of an immune-suppressive, “cold” TME [16]. The mechanisms of MYC dysregulation, including gene amplification and translocation, are activated by several key signaling pathways in cancer, such as the PI3K and RAS pathways [17,18]. Moreover, the interacting proteins of MYC enable the dysregulation of MYC to be maintained and its function to be enhanced [19]. For example, by phosphorylating MYC at serine 67, Aurora B counteracts the GSK3β-induced phosphorylation at threonine 58 and the subsequent proteasomal degradation mediated by FBXW7 [20]. The G9a histone methyltransferase interacts with MYC to drive transcriptional repression and tumorigenesis [21]. In summary, various mechanisms enhance the function of MYC, allowing this powerful transcription factor to promote cancer development in numerous human cancers (Figure 2). The overexpression of MYC has been observed to have an impact on crucial biological processes, including apoptosis and DNA repair, consequently elevating the likelihood of malignant transformation [22]. In addition to its direct involvement in promoting cancer, MYC has been linked to various tumor characteristics. For example, MYC overexpression has been found to facilitate tumor angiogenesis, tumor cell invasion, and metastasis [23]. Furthermore, MYC has the ability to modulate metabolic pathways in tumor cells, enabling them to adapt to environments characterized by low oxygen levels, limited nutrients, and acidity [24,25]. Consequently, in modern cancer research, developing strategies to target MYC has gained significant attention [26].
In preclinical studies, two main strategies have been employed to modulate MYC: (1) the use of the Tet system for conditional regulation of a MYC transgene [27,28,29,30,31,32] and (2) the use of a synthetic MYC inhibitor (Omomyc [33,34,35] or MYCi361 [36]) for conditional expression. Surprisingly, in these studies, preventing MYC dysregulation not only inhibited further tumor development but also led to rapid tumor regression, a phenomenon referred to as oncogene addiction. However, in certain types of tumors, such as pancreatic cancer, knockdown of MYC does not result in tumor cell apoptosis in vitro. This may be due to the absence of the complex TME consisting of tumor cells, stromal interactions, and infiltrating immune cells. In contrast, in vivo, blocking MYC expression results in rapid tumor decrease. [32,37]. This phenomenon suggests that targeting MYC may play a critical role in regulating cell-cell interactions, particularly interactions between tumor cells and immune cells, thereby enabling tumor cells to establish a more favorable TME. Therefore, in this review, we emphasize the critical role of MYC and MYC-associated oncogenic signaling in tumor immunity and explore potential strategies for targeting MYC in conjunction with immunotherapy. We also propose that targeting MYC-interacting proteins to regulate the expression and function of MYC as an alternative strategy for direct targeting of MYC enables combination therapies to achieve clinical transformation more rapidly.

2. MYC and Tumor Immune Escape

Tumor immune evasion refers to the strategies employed by cancer cells to avoid detection and destruction by the host immune system, enabling their survival, proliferation, and metastasis. It is well known that these directly contribute to tumor formation and significantly influence tumor reduction when deactivated (Figure 2). Recently, a detailed pan-cancer investigation identified ENC1 (ectodermal-neural cortex 1) as a potential prognostic biomarker for TME and treatment efficacy [38]. Of note, a study has shown that MYC is capable of directly binding to the promoter region of ECN1 and exerting direct regulation over its transcriptional activity [39]. Therefore, the efficacy of targeted MYC inhibition in suppressing tumor immune escape can be evaluated by monitoring the transcriptional levels of ENC1. However, further research is essential to elucidate the systemic characteristics of MYC-targeted inhibition of tumor immune escape, thereby enabling the prediction of the prognosis of MYC-targeted therapy combined with immunotherapy across various cancer types, similar to the TGF-β signaling-related lncRNA signature identified by Wei-wei et al. [40]. Prior to this, we can systematically examine the multifaceted influence of MYC on immune cell infiltration and antitumor cytotoxicity within the TME.

2.1. MYC Mediates the Escape of Tumor Cells from T-Cell Immunity

In 2016, Stephanie et al. reported that MYC suppression in tumors from mice and humans lowered the levels of programmed death-ligand 1 (PD-L1) mRNA and protein [41,42]. PD-L1, also referred as CD274 or B7-H1, serves as an essential “do not find me” signal to the adaptive immune system, eliminating T-cell hostility by binding to programmed death 1 (PD-1) on T cells [43,44,45]. The PD-1 protein functions as a coinhibitory receptor and is associated with two ligands, PD-L1 and PD-L2 (B7-DC) [46,47,48,49]. Preventing PD-1 from interacting with PD-L1 strengthens immune responses in vitro and contributes to antitumor activity in preclinical experiments [50]. At present, antibodies targeting PD-1 and PD-L1 are recognized as standard care for initial cancer treatment.
Nevertheless, the response rates of just 15–50% in various solid tumors, along with high rates of progression and relapse, indicate that resistance mechanisms frequently hinder effective tumor management [51]. Transforming growth factor-β (TGF-β), a tolerogenic factor, is commonly used by cancer cells to avoid immune responses [52,53]. Growth differentiation factor 15 (GDF-15), a TGF-β superfamily produced in large quantities by various cancer types, can disrupt the antitumor immune response. Tumor-derived GDF-15 inhibits the adhesion and movement of effector T-cells into the tumor microenvironment [48]. In preclinical cancer models, blocking GDF-15 synergistically improved the effectiveness of anti-PD-1 [54]. Moreover, a clinical trial demonstrated that co-administering the GDF-15-blocking antibody visugromab with the nivolumab can counteract resistance to anti-PD-1 [51]. Following 2 weeks of anti-GDF-15 monotherapy, T-cell infiltration, growth, and activation as well as the induction of interferon-related genes and pathways within the TME [51]. At present, visugromab underwent its first human trial in a combined phase 1 and 2a study (CTL-002-001; NCT04725474). Further research on GDF-15 is necessary to explore its role, identify predictive biomarkers, and understand its mechanisms and clinical implications.
Surprisingly, GDF-15 is also subject to transcriptional regulation by MYC. MYC improves the level of GDF-15 by attaching to the E-box sequences in the GDF-15 promoter, playing a role in the positive feedback loop of GDF-15/MYC/GDF-15 [55]. Taken together, these findings suggest that MYC targeting can substantially enhance T cell-mediated tumor cell destruction.

2.2. MYC Mediates the Escape of Tumor Cells from Macrophage Immunity

GDF-15 was first identified as a cytokine that inhibits macrophages, known as MIC-1 [56]. Therefore, the regulation of GDF-15 by MYC also promotes the escape of tumor cells from macrophage attack. Moreover, in 2016, Stephanie et al. also reported that reducing MYC in mouse tumors and human cancer cells led to decreased levels of CD47 mRNA and protein [41,42]. Chromatin immunoprecipitation sequencing (ChIP-Seq) demonstrated that MYC binds to the promoters of CD47 and PD-L1, mechanistically [33,34]. CD47 is a critical “do not eat me” signal to the innate immune system as well as a regulator of the adaptive immune response [57,58]. CD47 on the tumor cell surface interacts with inhibitory macrophage receptor signal regulatory protein α (SIRPα) to send a signal that inhibits phagocytosis, preventing cancer cells from being cleared by macrophages [48,49]. Moreover, CD47 promotes tumor progression in various malignancies by interacting with thrombospondin-1 (TSP-1) [59].
In addition to directly regulating the expression of CD47, MYC may further help tumor cells escape phagocytosis by regulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme in arginine biosynthesis [60] (Figure 3). Arginine is a semi-essential amino acid that the body can produce internally, but it often needs to be supplemented from external sources, especially during growth, wound recovery, or in tumors with reduced arginine production. It plays a role in protein synthesis, cell growth, and immune system regulation [61]. Keshet et al. demonstrated that ASS1 expression is induced by MYC under glucose deprivation [62]. Another study indicates that MYC transcriptionally regulates ASS1 reactivation through the upstream Gas6-Axl tyrosine kinase (RTK) signaling pathway [63]. Moreover, our RNA-seq data obtained from the pancreatic cancer cell line Mia-Paca2 revealed a substantial reduction in ASS1 mRNA levels following MYC knockdown. ASS1 downregulation promotes cell proliferation in various tumors; its expression correlates with poor prognosis in several common cancer subsets [62]. Decreasing ASS1 allows more aspartate to be used in pyrimidine synthesis, thereby supporting cell proliferation [64]. However, increased pyrimidine levels result in a mutational bias towards pyrimidine, which is connected to elevated hydrophobic-immunogenic antigens and a heightened response to immunotherapy [65]. In a recent study, Yinghua et al. highlighted the significant role of metabolic interactions between cancer cells and macrophages in promoting arginine-driven breast cancer progression [66]. Taken together, targeting MYC significantly enhances macrophage-mediated tumor cell destruction.

2.3. MYC May Mediate Immune Escape of Tumor Cells by Inducing Neutrophil Infiltration

Neutrophils that are pathologically activated, known as myeloid-derived suppressor cells (PMN-MDSCs), play a significant role in suppressing antitumor immunity [67,68,69]. It is known that MYC promotes neutrophil infiltration in the external tumor environment [70]. For example, in a zebrafish liver tumor model study, the phenomenon of MYC overexpression, which incurred an increase in liver-infiltrated neutrophils, was successfully observed [70]. Moreover, MYCN also modulates infiltration of neutrophils through attenuation of NF-kappaB signaling by activating NDRG1/Cap43 pathway [71]. Recent research has shown that neutrophils physically interact with tumor cells to form a signaling niche that promotes breast cancer aggressiveness [72]. A separate study demonstrated that co-culturing renal cell carcinoma (RCC) cells with neutrophils can specifically impact MYC signaling, thereby promoting RCC cell proliferation [73]. These findings suggest that MYC facilitates tumor development by recruiting neutrophils to infiltrate the TME. Nevertheless, the question remains whether neutrophils within the TME contribute to the immune evasion of tumor cells. This topic will be briefly explored in the subsequent discussion.
Rina et al. demonstrated that PMN-MDSCs in the TME die spontaneously via ferroptosis [74]. Ferroptosis is a type of regulated cell death that is not apoptotic, initiated by the imbalance of redox regulatory processes, leading to extensive peroxidation of polyunsaturated phospholipids. In addition, by lowering PMN-MDSCs, ferroptosis promotes the release of oxygenated lipids and curtails T-cell activity in mice and humans [74]. In mouse models of spontaneous tumor development, interfering with IL-1β+ CD4+ T cells or IL-1R1+ neutrophils interrupted communication, reduced neutrophil ferroptosis, boosted antitumor immunity, and countered chemoresistance [75]. Therefore, inhibiting the ferroptosis of neutrophils is beneficial for immune cells to kill tumor cells. Taken together, neutrophils in the TME may promote immune escape of tumor cells through spontaneous ferroptosis.
Of note, the regulation of ferroptosis by MYC has been widely reported. For example, MYC enhances cellular antioxidant capacity and suppresses ferroptosis in cancer stem cells by activating CPT1A expression, which in turn activates the NRF2/GPX4 system and reduces phospholipid polyunsaturated fatty acids via ACSL4 downregulation [76]. Moreover, MYC directly downregulates the expression of NCOA4, thereby inhibiting ferroptosis, promoting ovarian cancer cells’ malignant phenotype and immune evasion by suppressing ferritin autophagy [77]. Furthermore, MYC reduces the inhibition of pan-death, including ferroptosis, in colorectal cancer tumor cells by transcriptionally regulating NFS1, thereby decreasing their chemosensitivity [78]. These studies have shown that MYC inhibits ferroptosis in tumor cells and is an important cause of ferroptosis resistance in tumors [79,80]. However, a limited number of studies have also suggested that MYC plays a role in promoting ferroptosis. For example, Hamed et al. demonstrated that MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis [81]. Moreover, the upregulation of ACSL4 by MYC, driven by oncogenic RTKs, increases cancer cells’ sensitivity to ferroptosis [82]. The variations in the regulatory effect of MYC on ferroptosis across different tumor cells may be attributed to the distinct characteristics of oncogenes and the heterogeneity of the TME. In treatment-naive high-grade serous ovarian cancer (HGSOC), investigating TME cell composition, DNA copy number, mutations, and gene expression demonstrated that immune cell exclusion correlated with the amplification of MYC target genes [83]. However, unfortunately, no studies have reported whether MYC exerts a regulatory effect on ferroptosis in neutrophils. Moreover, tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type [84]. Therefore, investigating the role of MYC in regulating ferroptosis in neutrophils across different cancers may represent a significant research gap that warrants further exploration. Specific experiments to test if MYC regulates key ferroptosis drivers (GPX4, ACSL4, etc.) specifically in PMN-MDSCs/TANs are necessary and meaningful. To summarize, these findings indicate that targeting MYC to attenuate neutrophil infiltration within the TME can not only suppress tumor cell proliferation and invasion but may also contribute to inhibiting tumor immune escape.

2.4. MYC Mediates the Escape of Tumor Cells from Natural Killer (NK) Cells Immunity

NK cells, which have cytotoxic functions similar to those of CD8+ T cells, are another powerful weapon against tumors. Deactivating MYC in existing adenocarcinomas immediately reverses stromal changes and causes tumor regression, which is not dependent on CD4+CD8+ T cells but heavily relies on the return of NK cells [85]. Research has further revealed that MYC-dependent tumor progression requires IL-23 signaling to NK cells, thereby promoting the exclusion of NK cells from the TME [85]. IL-23 is a proinflammatory cytokine that hinders wound healing and promotes tumor growth in various tissues [86]. It also strongly inhibits innate immunity, particularly affecting NK cells [87]. The absence of IL-23 in mice led to resistance against experimental tumor metastases in three models, where host NK cells were responsible for disease control [87]. IL-23 has been shown to be positively regulated by MYC [88,89]. For instance, the increased expression of IL-23 observed in Mst1-knockdown dendritic cells (DCs) was effectively downregulated by MYC inhibitors [89]. Moreover, inactivation of MYC also increases the level of NKG2DL in N-type small cell lung cancer (SCLC-N) cells, resulting in NK cell recruitment [90]. Originally found in NK cells, NKG2D identifies ligands that are elevated on cancer cells [91]. MYC-MIZ1 repressive complexes bind directly to the promoters of the genes encoding the type I IFN regulators to inhibit the expression of these genes, such as STAT1, STAT2, IRF5, and IRF7 [92]. Moreover, derepression of IFN regulator genes facilitates the infiltration of pancreatic tumors by B and natural killer cells, resulting in increased survival [92]. Taken together, MYC in tumor cells appears to reduce the number of NK cells in the TME through a number of mechanisms.

3. Strategies Combining the Targeting of MYC and Immunotherapy

3.1. Inhibition of MYC Combined with Cell Therapy

Previously, we discussed the regulatory role of MYC in tumor immune escape. On the basis of these studies, we discuss possible strategies for targeting MYC in combination with immunotherapy (Figure 4). First, MYC has been found to upregulate the expression of the immune checkpoint PD-L1, thus leading to T-cell exhaustion [41,85,93,94,95]. Of note, the inhibition of MYC results in the expression of PD-L1 decreasing significantly, thereby increasing the number of surviving T cells in the TME. In addition, targeting MYC can significantly increase the proportion of CD8+ T cells, thereby enhancing the killing effect of T cells on tumor cells [36]. Therefore, targeting MYC can be combined with chimeric antigen receptor-modified T (CAR-T) cell therapy to replenish exhausted T cells in the TME. CAR-T cell therapy has been highly successful in treating blood cancers, but it is less effective against solid tumors, partly because of CAR-T cell exhaustion in the solid tumor microenvironment [96]. Moreover, genetic downregulation of ID3 and SOX4 expression can improve the efficacy of CAR-T cell therapy in solid tumors by preventing or delaying CAR-T cell dysfunction [96]. ID3 and SOX4 are positively regulated by MYC [97,98]. Therefore, inhibition of MYC in cancer cells can promote the therapeutic effect of CAR-T cells on solid tumors.
In addition to CAR-T cells, CAR-NK cells have become a research hotspot since 2025 because of their “off-the-shelf” characteristics. It has been confirmed in multiple mouse models that CAR/IL-15 NK cells from optimal cord blood units (CBUs) in vivo have superior antitumor activity [99]. Jianhua et al. demonstrated that neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via MYC/NRF1 activation [100]. The findings indicate that MYC is essential for Neo-2/15-driven ATP generation by CAR-NK cells in the TME [100]. Moreover, Daher et al. reported a strategy that combines the targeting of the cytokine-inducible Src homology 2-containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation “armored” CAR engineering of cord blood-derived NK cells [98]. The combined strategy enhances NK cell effectiveness by promoting the Akt/mTORC1 pathway and MYC signaling, which increases aerobic glycolysis [101]. Moreover, through transcriptome and chromatin immunoprecipitation analysis, MYC was identified as a direct downstream target of XBP1, playing a role in NK cell proliferation regulation [102]. Taken together, these findings suggest that enhancing MYC signaling within CAR-NK cells may increase their therapeutic efficacy.

3.2. Inhibition of MYC Combined with Monoclonal Antibodies

In addition to regulating PD-L1, MYC has also been identified as a transcription factor for GDF-15 [55]. Targeting GDF-15 has been shown to overcome the resistance associated with PD-1/PD-L1 monoclonal antibody therapy [51]. Consequently, targeting MYC in combination with PD-1/PD-L1 monoclonal antibodies may serve as a promising therapeutic strategy. The application of PD1/PD-L1 monoclonal antibodies in combination with MYC inhibition not only aids in overcoming drug resistance but also decreases the required dosage of PD1/PD-L1 monoclonal antibodies. Moreover, antibodies targeting the immune checkpoint molecules PD-1, PD-L1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4), administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small cell lung cancers and other cancers [103,104]. Of note, dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 has achieved remarkable success in various cancers [105,106,107,108]. In light of the positive regulatory effect of MYC on PD-L1, inhibition of MYC in combination with CTLA-4 monoclonal antibodies may serve as an optional therapeutic strategy.
As elucidated in the preceding sections, MYC-driven macrophage immune evasion primarily involves the transcriptional upregulation of CD47, which collectively suppresses phagocytic activity and creates an immunosuppressive microenvironment [51]. The dual blockade of galectin-3 (Gal-3) and CD47 synergistically suppressed tumor growth, increased phagocytosis, repolarized macrophages, and increased T-cell immune responses [106]. However, depletion of Gal-3 reduces the expression of CD47 through inhibition of the binding of MYC to the CD47 promoter [109]. Therefore, targeting MYC in combination with CD47 monoclonal antibodies may also serve as a promising therapeutic strategy.

3.3. Inhibition of MYC Combined with Adjustment for Nutritional Intake

Cancer cells rewire metabolism to favor the generation of specialized metabolites that support tumor growth and reshape the tumor microenvironment [110,111]. A recent study reported that a lysine-restricted (LR) diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumor growth [112]. Mechanically, LR diet enhances IFN signalling and functional CD8+ T cell infiltration [112]. This study successfully established a connection between targeting MYC and dietary and nutritional interventions. However, the efficacy of the LR diet has only been demonstrated at the animal experimentation stage, and significant further research is required before this strategy can be translated into clinical application. Moreover, whether restricting other single amino acids may similarly facilitate tumor immune escape. For example, breast cancer cells promote tumor-associated macrophage polarization via arginine secretion, thereby suppressing CD8+ T cell cytotoxicity against tumors [66]. Therefore, dietary arginine restriction may enhance immune-mediated tumor cell killing. In light of the regulatory influence of MYC on ASS1, targeting MYC and inhibiting arginine uptake may offer greater therapeutic benefits for breast cancer patients [66]. Moreover, Cao et al. suggested that tumoral SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies [113]. SLC6A6 may be directly or indirectly regulated by MYC [113,114]. Therefore, targeting MYC and taurine supplementation may enhance the tumor-killing capacity of immune cells. Beyond amino acids, vitamins have garnered increasing attention for their multifaceted roles in cancer treatment, with accumulating evidence supporting their potential in prevention, adjuvant therapy, and immunomodulation. A recent study revealed that cancer cells exploit circulating lipoproteins to acquire α-tocopherol (the predominant form of vitamin E in human lipoproteins), thereby mitigating lipid peroxidation toxicity and enhancing resistance to ferroptosis [115]. Moreover, A clinical study investigating breast cancer has demonstrated that supplementing with a low dose of vitamin D can enhance the efficacy of chemotherapy in breast cancer patients. Specifically, patients who received a daily supplementation of 2000 IU of vitamin D for six months showed a pathological complete response rate of 43% in the vitamin D supplementation group [116]. However, whether the selective uptake of vitamin components and the targeting of MYC exhibit a synergistic effect has not yet been systematically investigated to date. This area of research may hold significant potential for further exploration. Taken together, strategic modulation of MYC signaling pathways coupled with tailored nutritional interventions may constitute a multimodal paradigm with substantial translational potential for cancer therapeutics. Of note, given the substantial complexity and heterogeneity of the TME, whether restricting a single nutrient intake suffices to elicit desired therapeutic outcomes or whether combined targeting of MYC enhances efficacy requires rigorous experimental validation.

4. Future Directions

Insights into the regulatory role of MYC in the host immune response hold significant practical implications for the development of therapeutics and the strategic selection of therapies. Targeting MYC, either alone or in conjunction with immunotherapy, is anticipated to offer a curative approach for a majority of cancers. However, as of now, no direct MYC inhibitors have received approval for clinical use. Consequently, the development of effective and safe strategies to suppress MYC expression in cancer cells remains a critical challenge. This necessitates innovative approaches to mitigate its pleiotropic oncogenic functions while minimizing off-target effects. The development of targeted therapies aimed at disrupting the oncogenic functions of MYC has become a central focus in cancer research, with particular emphasis on modulating MYC-interacting protein networks. This strategy is exemplified by recent advancements in destabilizing MYC-MAX heterodimers through engineered peptides, such as Omomyc, and proteolysis-targeting chimeras (PROTACs), which induce MYC degradation [117,118]. Moreover, strategies targeting MYC transcriptional regulation, translational control, protein stability, and transcriptional activity have now been proposed (Table 1). In 2020, Lourenço C et al. systematically reviewed the therapeutic strategies targeting MYC, which we only briefly touch upon in this context [19].
Notably, MYC-mediated immune evasion is characterized by tumor type-specific mechanistic heterogeneity, necessitating tailored combinatorial immunotherapies that target distinct immune suppressive pathways. Therefore, the identification of biomarkers capable of predicting prevalent MYC-driven immune escape mechanisms in individual patients and tumor types is essential to guide personalized combinatorial therapeutic strategies. Of note, owing to MYC’s pleiotropic regulation of cellular processes, targeting MYC represents a promising strategy to overcome immunotherapy resistance [119,120]. Therefore, directly targeting MYC remains the most critical challenge to overcome in current oncology therapeutics. Moreover, the development of additional preclinical models is imperative to rigorously evaluate the efficacy of combinatorial therapeutic regimens and derive clinically actionable treatment strategies. Our strategy should first assess whether MYC targeting modulates immune cell infiltration in the TME or enhances the antitumor activity of immune cells. Based on these findings, we can then rationally select combination therapies. Bioinformatics analysis may further guide the selection of appropriate preclinical models to validate these hypotheses. In summary, as our understanding of MYC biology has increased and immunotherapeutic strategies, such as immune checkpoint blockade, have demonstrated clinical efficacy in treating hematologic malignancies, we have positive hopes for the future.
Table 1. Main strategies targeting MYC in cancer therapy.
Table 1. Main strategies targeting MYC in cancer therapy.
StrategiesRepresentative TargetPromising Therapeutic AgentsReferences
MYC-MAX dimerization disruptionMYC-MAXOmomyc[98]
KSI-3716[121]
MYCi361/MYCi975[36]
VPC-70067[122]
10058-F4[123]
IIA6B17[124]
10074-G5[125]
MYCMI-6[126]
H1 peptide[127]
MI1-PD[128]
KJ-Pyr-9[129]
Mycro3[130]
Disrupt the binding of MYC-DNAMYC-DNAME47[131]
Transcriptional and
translational suppression		CDK7SNS-032[132]
CDK9AZD4573[133]
BRD4JQ-1[134]
Targeting interacting proteinsAURKBAZD-1152[19,135]
WDR5C6[136]
EZH2Tazemetostat[137]
Targeting the
upstream signaling pathways		RASRMC-7977[138]

Author Contributions

Z.H. wrote the manuscript, and everyone reviewed it. X.L., Z.S. and W.Z. proposed revision suggestions. Z.H. and S.M., co-first authors, contributed equally to this work. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from the Key/Major Project of Jianhu Clinical College of Jiangsu Vocational College of Medicine (20229JH03, 202490202) and the National Natural Science Foundation of China (82373160).

Data Availability Statement

Not Applicable.

Conflicts of Interest

The authors declare that they have no competing interests.

References

  1. Kress, T.R.; Sabò, A.; Amati, B. MYC: Connecting selective transcriptional control to global RNA production. Nat. Rev. Cancer 2015, 15, 593–607. [Google Scholar] [CrossRef] [PubMed]
  2. Conacci-Sorrell, M.; McFerrin, L.; Eisenman, R.N. An overview of MYC and its interactome. Cold Spring Harb. Perspect. Med. 2014, 4, a014357. [Google Scholar] [CrossRef]
  3. Tansey, W.P. Mammalian MYC proteins and cancer. New J. Sci. 2014, 2014, 1–27. [Google Scholar] [CrossRef]
  4. Casey, S.C.; Baylot, V.; Felsher, D.W. The MYC oncogene is a global regulator of the immune response. Blood 2018, 131, 2007–2015. [Google Scholar] [CrossRef] [PubMed]
  5. Di Giacomo, S.; Sollazzo, M.; Paglia, S.; Grifoni, D. MYC, cell competition, and cell death in cancer: The inseparable triad. Genes 2017, 8, 120. [Google Scholar] [CrossRef]
  6. Stine, Z.E.; Walton, Z.E.; Altman, B.J.; Hsieh, A.L.; Dang, C.V. MYC, metabolism, and cancer. Cancer Discov. 2015, 5, 1024–1039. [Google Scholar] [CrossRef]
  7. Yoshida, G.J. Emerging roles of Myc in stem cell biology and novel tumor therapies. J. Exp. Clin. Cancer Res. 2018, 37, 173. [Google Scholar] [CrossRef]
  8. Dang, C.V.; O’Donnell, K.A.; Zeller, K.I.; Nguyen, T.; Osthus, R.C.; Li, F. The c-Myc target gene network. Semin. Cancer Biol. 2006, 16, 253–264. [Google Scholar] [CrossRef]
  9. Williamson, D.; Lu, Y.J.; Gordon, T.; Sciot, R.; Kelsey, A.; Fisher, C.; Poremba, C.; Anderson, J.; Pritchard-Jones, K.; Shipley, J. Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in the alveolar subtype. J. Clin. Oncol. 2005, 23, 880–888. [Google Scholar] [CrossRef]
  10. Williams, R.D.; Al-Saadi, R.; Natrajan, R.; Mackay, A.; Chagtai, T.; Little, S.; Hing, S.N.; Fenwick, K.; Ashworth, A.; Grundy, P.; et al. Molecular profiling reveals frequent gain of MYCN and anaplasia-specific loss of 4q and 14q in Wilms tumor. Genes Chromosomes Cancer 2011, 50, 982–995. [Google Scholar] [CrossRef]
  11. Berger, A.; Brady, N.J.; Bareja, R.; Robinson, B.; Conteduca, V.; Augello, M.A.; Puca, L.; Ahmed, A.; Dardenne, E.; Lu, X.; et al. N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. J. Clin. Investig. 2019, 129, 3924–3940. [Google Scholar] [CrossRef] [PubMed]
  12. Rickman, D.S.; Schulte, J.H.; Eilers, M. The expanding world of N-MYC–driven tumors. Cancer Discov. 2018, 8, 150–163. [Google Scholar] [CrossRef] [PubMed]
  13. Cheng, J.; Park, D.E.; Berrios, C.; White, E.A.; Arora, R.; Yoon, R.; Branigan, T.; Xiao, T.; Westerling, T.; Federation, A.; et al. Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis. PLoS Pathog. 2017, 13, e1006668. [Google Scholar] [CrossRef] [PubMed]
  14. Ohshima, K.; Hatakeyama, K.; Nagashima, T.; Watanabe, Y.; Kanto, K.; Doi, Y.; Ide, T.; Shimoda, Y.; Tanabe, T.; Ohnami, S.; et al. Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors. Sci. Rep. 2017, 7, 641. [Google Scholar] [CrossRef]
  15. Boutros, P.C.; Fraser, M.; Harding, N.J.; de Borja, R.; Trudel, D.; Lalonde, E.; Meng, A.; Hennings-Yeomans, P.H.; McPherson, A.; Sabelnykova, V.Y.; et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat. Genet. 2015, 47, 736–745. [Google Scholar] [CrossRef]
  16. Thege, F.I.; Rupani, D.N.; Barathi, B.B.; Manning, S.L.; Maitra, A.; Rhim, A.D.; Wörmann, S.M. A Programmable In Vivo CRISPR Activation Model Elucidates the Oncogenic and Immunosuppressive Functions of MYC in Lung Adenocarcinoma. Cancer Res. 2022, 82, 2761–2776. [Google Scholar] [CrossRef]
  17. Meyer, N.; Penn, L.Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer 2008, 8, 976–990. [Google Scholar] [CrossRef]
  18. Kalkat, M.; De Melo, J.; Hickman, K.A.; Lourenco, C.; Redel, C.; Resetca, D.; Tamachi, A.; Tu, W.B.; Penn, L.Z. MYC deregulation in primary human cancers. Genes 2017, 8, 151. [Google Scholar] [CrossRef]
  19. Lourenco, C.; Resetca, D.; Redel, C.; Lin, P.; MacDonald, A.S.; Ciaccio, R.; Kenney, T.M.G.; Wei, Y.; Andrews, D.W.; Sunnerhagen, M.; et al. MYC protein interactors in gene transcription and cancer. Nat. Rev. Cancer 2021, 21, 579–591. [Google Scholar] [CrossRef]
  20. Jiang, J.; Wang, J.; Yue, M.; Cai, X.; Wang, T.; Wu, C.; Su, H.; Wang, Y.; Han, M.; Zhang, Y.; et al. Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis. Cancer Cell 2020, 37, 200–215.e5. [Google Scholar] [CrossRef]
  21. Tu, W.B.; Shiah, Y.J.; Lourenco, C.; Mullen, P.J.; Dingar, D.; Redel, C.; Tamachi, A.; Ba-Alawi, W.; Aman, A.; Al-Awar, R.; et al. MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis. Cancer Cell 2018, 34, 579–595.e8. [Google Scholar] [CrossRef]
  22. Qu, A.; Jiang, C.; Cai, Y.; Kim, J.H.; Tanaka, N.; Ward, J.M.; Shah, Y.M.; Gonzalez, F.J. Role of Myc in hepatocellular proliferation and hepatocarcinogenesis. J. Hepatol. 2014, 60, 331–338. [Google Scholar] [CrossRef]
  23. Qin, N.; Paisana, E.; Langini, M.; Picard, D.; Malzkorn, B.; Custódia, C.; Cascão, R.; Meyer, F.D.; Blümel, L.; Göbbels, S.; et al. Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis. Neuro Oncol. 2022, 24, 1509–1523. [Google Scholar] [CrossRef] [PubMed]
  24. Gwynne, W.D.; Suk, Y.; Custers, S.; Mikolajewicz, N.; Chan, J.K.; Zador, Z.; Chafe, S.C.; Zhai, K.; Escudero, L.; Zhang, C.; et al. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. Cancer Cell 2022, 40, 1488–1502.e7. [Google Scholar] [CrossRef] [PubMed]
  25. Gnanaprakasam, J.N.R.; Sherman, J.W.; Wang, R. MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev. 2017, 35, 63–70. [Google Scholar] [CrossRef]
  26. Dang, C.V. MYC on the path to cancer. Cell 2012, 149, 22–35. [Google Scholar] [CrossRef]
  27. Jain, M.; Arvanitis, C.; Chu, K.; Dewey, W.; Leonhardt, E.; Trinh, M.; Sundberg, C.D.; Bishop, J.M.; Felsher, D.W. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 2002, 297, 102–104. [Google Scholar] [CrossRef]
  28. Shroff, E.H.; Eberlin, L.S.; Dang, V.M.; Gouw, A.M.; Gabay, M.; Adam, S.J.; Bellovin, D.I.; Tran, P.T.; Philbrick, W.M.; Garcia-Ocana, A.; et al. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc. Natl. Acad. Sci. USA 2015, 112, 6539–6544. [Google Scholar] [CrossRef] [PubMed]
  29. Felsher, D.W.; Bishop, J.M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 1999, 4, 199–207. [Google Scholar] [CrossRef]
  30. Wu, C.H.; van Riggelen, J.; Yetil, A.; Fan, A.C.; Bachireddy, P.; Felsher, D.W. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc. Natl. Acad. Sci. USA 2007, 104, 13028–13033. [Google Scholar] [CrossRef]
  31. Lourenco, C.; Kalkat, M.; Houlahan, K.E.; De Melo, J.; Longo, J.; Done, S.J.; Boutros, P.C.; Penn, L.Z. Modeling the MYC-driven normal-to-tumor switch in breast cancer. Dis. Model. Mech. 2019, 12, dmm038083. [Google Scholar] [CrossRef] [PubMed]
  32. Sodir, N.M.; Kortlever, R.M.; Barthet, V.J.A.; Campos, T.; Pellegrinet, L.; Kupczak, S.; Anastasiou, P.; Swigart, L.B.; Soucek, L.; Arends, M.J.; et al. MYC instructs and maintains pancreatic adenocarcinoma phenotype. Cancer Discov. 2020, 10, 588–607. [Google Scholar] [CrossRef] [PubMed]
  33. Soucek, L.; Whitfield, J.R.; Sodir, N.M.; Massó-Vallés, D.; Serrano, E.; Karnezis, A.N.; Swigart, L.B.; Evan, G.I. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 2013, 27, 504–513. [Google Scholar] [CrossRef]
  34. Jung, L.A.; Gebhardt, A.; Koelmel, W.; Ade, C.P.; Walz, S.; Kuper, J.; von Eyss, B.; Letschert, S.; Redel, C.; d’Artista, L.; et al. OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors. Oncogene 2017, 36, 1911–1924. [Google Scholar] [CrossRef]
  35. Demma, M.J.; Mapelli, C.; Sun, A.; Bodea, S.; Ruprecht, B.; Javaid, S.; Wiswell, D.; Muise, E.; Chen, S.; Zelina, J.; et al. Omomyc reveals new mechanisms to inhibit the MYC oncogene. Mol. Cell Biol. 2019, 39, e00248-19. [Google Scholar] [CrossRef]
  36. Han, H.; Jain, A.D.; Truica, M.I.; Izquierdo-Ferrer, J.; Anker, J.F.; Lysy, B.; Sagar, V.; Luan, Y.; Chalmers, Z.R.; Unno, K.; et al. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell 2019, 36, 483–497.e15. [Google Scholar] [CrossRef]
  37. English, I.A.; Sears, R.C. Deconstructing Pancreatic Adenocarcinoma by Targeting the Conductor, MYC. Cancer Discov. 2020, 10, 495–497. [Google Scholar] [CrossRef] [PubMed]
  38. Cao, Z.; Zhu, J.; Wang, Z.; Peng, Y.; Zeng, L. Comprehensive pan-cancer analysis reveals ENC1 as a promising prognostic biomarker for tumor microenvironment and therapeutic responses. Sci. Rep. 2024, 14, 25331. [Google Scholar] [CrossRef]
  39. Li, X.; Zhao, H.; Liu, J.; Tong, J. Long Non-coding RNA MIAT Knockdown Prevents the Formation of Intracranial Aneurysm by Downregulating ENC1 via MYC. Front. Physiol. 2021, 11, 572605. [Google Scholar] [CrossRef]
  40. Duan, W.W.; Yang, L.T.; Liu, J.; Dai, Z.Y.; Wang, Z.Y.; Zhang, H.; Zhang, X.; Liang, X.S.; Luo, P.; Zhang, J.; et al. A TGF-β signaling-related lncRNA signature for prediction of glioma prognosis, immune microenvironment, and immunotherapy response. CNS Neurosci. Ther. 2024, 30, e14489. [Google Scholar] [CrossRef]
  41. Casey, S.C.; Tong, L.; Li, Y.; Do, R.; Walz, S.; Fitzgerald, K.N.; Gouw, A.M.; Baylot, V.; Gütgemann, I.; Eilers, M.; et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016, 352, 227–231. [Google Scholar] [CrossRef] [PubMed]
  42. MYC Promotes Tumorigenesis via Activation of CD47 and PD-L1. Cancer Discov. 2016, 6, 472. [CrossRef] [PubMed]
  43. Parsa, A.T.; Waldron, J.S.; Panner, A.; Crane, C.A.; Parney, I.F.; Barry, J.J.; Cachola, K.E.; Murray, J.C.; Tihan, T.; Jensen, M.C.; et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 2007, 13, 84–88. [Google Scholar] [CrossRef]
  44. Topalian, S.L.; Drake, C.G.; Pardoll, D.M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 2012, 24, 207–212. [Google Scholar] [CrossRef]
  45. Tsushima, F.; Yao, S.; Shin, T.; Flies, A.; Flies, S.; Xu, H.; Tamada, K.; Pardoll, D.M.; Chen, L. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 2007, 110, 180–185. [Google Scholar] [CrossRef]
  46. Dong, H.; Zhu, G.; Tamada, K.; Chen, L. B7-H1, a third member of the B7 family, costimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 1999, 5, 1365–1369. [Google Scholar] [CrossRef]
  47. Freeman, G.J.; Long, A.J.; Iwai, Y.; Bourque, K.; Chernova, T.; Nishimura, H.; Fitz, L.J.; Malenkovich, N.; Okazaki, T.; Byrne, M.C.; et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 2000, 192, 1027–1034. [Google Scholar] [CrossRef] [PubMed]
  48. Tseng, S.Y.; Otsuji, M.; Gorski, K.; Huang, X.; Slansky, J.E.; Pai, S.I.; Shalabi, A.; Shin, T.; Pardoll, D.M.; Tsuchiya, H. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 2001, 193, 839–846. [Google Scholar] [CrossRef]
  49. Latchman, Y.; Wood, C.R.; Chernova, T.; Chaudhary, D.; Borde, M.; Chernova, I.; Iwai, Y.; Long, A.J.; Brown, J.A.; Nunes, R.; et al. PD-L2 is a second ligand for PD-1 and inhibits T-cell activation. Nat. Immunol. 2001, 2, 261–268. [Google Scholar] [CrossRef]
  50. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef]
  51. Melero, I.; de Miguel Luken, M.; de Velasco, G.; Garralda, E.; Martín-Liberal, J.; Joerger, M.; Alonso, G.; Goebeler, M.E.; Schuler, M.; König, D.; et al. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumors. Nature 2025, 637, 1218–1227. [Google Scholar] [CrossRef] [PubMed]
  52. Batlle, E.; Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 2019, 50, 924–940. [Google Scholar] [CrossRef]
  53. Lodyga, M.; Hinz, B. TGF-β1—A truly transforming growth factor in fibrosis and immunity. Semin. Cell Dev. Biol. 2020, 101, 123–139. [Google Scholar] [CrossRef] [PubMed]
  54. Haake, M.; Haack, B.; Schäfer, T.; Harter, P.N.; Mattavelli, G.; Eiring, P.; Vashist, N.; Wedekink, F.; Genssler, S.; Fischer, B.; et al. Tumor-derived GDF-15 blocks LFA-1 dependent T-cell recruitment and suppresses responses to anti-PD-1 treatment. Nat. Commun. 2023, 14, 4253. [Google Scholar] [CrossRef]
  55. Li, S.; Ma, Y.M.; Zheng, P.S.; Zhang, P. GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. J. Exp. Clin. Cancer Res. 2018, 37, 80. [Google Scholar] [CrossRef]
  56. Bootcov, M.R.; Bauskin, A.R.; Valenzuela, S.M.; Moore, A.G.; Bansal, M.; He, X.Y.; Zhang, H.P.; Donnellan, M.; Mahler, S.; Pryor, K.; et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc. Natl. Acad. Sci. USA 1997, 94, 11514–11519. [Google Scholar] [CrossRef]
  57. Jaiswal, S.; Jamieson, C.H.; Pang, W.W.; Park, C.Y.; Chao, M.P.; Majeti, R.; Traver, D.; van Rooijen, N.; Weissman, I.L. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009, 138, 271–285. [Google Scholar] [CrossRef] [PubMed]
  58. Majeti, R.; Chao, M.P.; Alizadeh, A.A.; Pang, W.W.; Jaiswal, S.; Gibbs, K.D., Jr.; van Rooijen, N.; Weissman, I.L. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009, 138, 286–299. [Google Scholar] [CrossRef]
  59. Kamijo, H.; Miyagaki, T.; Takahashi-Shishido, N.; Nakajima, R.; Oka, T.; Suga, H.; Sugaya, M.; Sato, S. Thrombospondin-1 promotes tumor progression in cutaneous T-cell lymphoma via CD47. Leukemia 2020, 34, 845–856. [Google Scholar] [CrossRef]
  60. Morris, S.M., Jr. Enzymes of arginine metabolism. J. Nutr. 2004, 134, 2743S–2767S. [Google Scholar] [CrossRef]
  61. Chen, C.L.; Hsu, S.C.; Ann, D.K.; Yen, Y.; Kung, H.J. Arginine Signaling and Cancer Metabolism. Cancers 2021, 13, 3541. [Google Scholar] [CrossRef] [PubMed]
  62. Keshet, R.; Lee, J.S.; Adler, L.; Iraqi, M.; Ariav, Y.; Lim, L.Q.J.; Lerner, S.; Rabinovich, S.; Oren, R.; Katzir, R.; et al. Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors. Nat. Cancer 2020, 1, 894–908. [Google Scholar] [CrossRef]
  63. Kuo, M.T.; Long, Y.; Tsai, W.B.; Li, Y.Y.; Chen, H.H.W.; Feun, L.G.; Savaraj, N. Collaboration Between RSK-EphA2 and Gas6-Axl RTK Signaling in Arginine Starvation Response That Confers Resistance to EGFR Inhibitors. Transl. Oncol. 2020, 13, 355–364. [Google Scholar] [CrossRef]
  64. Rabinovich, S.; Adler, L.; Yizhak, K.; Sarver, A.; Silberman, A.; Agron, S.; Stettner, N.; Sun, Q.; Brandis, A.; Helbling, D.; et al. Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. Nature 2015, 527, 379–383. [Google Scholar] [CrossRef]
  65. Lee, J.S.; Adler, L.; Karathia, H.; Carmel, N.; Rabinovich, S.; Auslander, N.; Keshet, R.; Stettner, N.; Silberman, A.; Agemy, L.; et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell 2018, 174, e1522. [Google Scholar] [CrossRef] [PubMed]
  66. Zhu, Y.; Zhou, Z.; Du, X.; Lin, X.; Liang, Z.M.; Chen, S.; Sun, Y.; Wang, Y.; Na, Z.; Wu, Z.; et al. Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion. Cancer Cell 2025, 43, 1045–1060.e7. [Google Scholar] [CrossRef] [PubMed]
  67. Condamine, T.; Mastio, J.; Gabrilovich, D.I. Transcriptional regulation of myeloid-derived suppressor cells. J. Leukoc. Biol. 2015, 98, 913–922. [Google Scholar] [CrossRef]
  68. Wang, W.; Xia, X.; Mao, L.; Wang, S. The CCAAT/Enhancer-Binding Protein Family: Its Roles in MDSC Expansion and Function. Front. Immunol. 2019, 10, 1804. [Google Scholar] [CrossRef]
  69. Ostrand-Rosenberg, S.; Beury, D.W.; Parker, K.H.; Horn, L.A. Survival of the fittest: How myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment. Cancer Immunol. Immunother. 2020, 69, 215–221. [Google Scholar] [CrossRef]
  70. Zhao, Y.; Huang, X.; Ding, T.W.; Gong, Z. Enhanced angiogenesis, hypoxia and neutrophil recruitment during Myc-induced liver tumorigenesis in zebrafish. Sci. Rep. 2016, 6, 31952. [Google Scholar] [CrossRef]
  71. Hosoi, F.; Izumi, H.; Kawahara, A.; Murakami, Y.; Kinoshita, H.; Kage, M.; Nishio, K.; Kohno, K.; Kuwano, M.; Ono, M. N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression. Cancer Res. 2009, 69, 4983–4991. [Google Scholar] [CrossRef]
  72. Camargo, S.; Moskowitz, O.; Giladi, A.; Levinson, M.; Balaban, R.; Gola, S.; Raizman, A.; Lipczyc, K.; Richter, A.; Keren-Khadmy, N.; et al. Neutrophils physically interact with tumor cells to form a signaling niche promoting breast cancer aggressiveness. Nat. Cancer 2025, 6, 540–558. [Google Scholar] [CrossRef] [PubMed]
  73. Song, W.; Li, L.; He, D.; Xie, H.; Chen, J.; Yeh, C.R.; Chang, L.S.; Yeh, S.; Chang, C. Infiltrating neutrophils promote renal cell carcinoma (RCC) proliferation via modulating androgen receptor (AR) → c-Myc signals. Cancer Lett. 2015, 368, 71–78. [Google Scholar] [CrossRef] [PubMed]
  74. Kim, R.; Hashimoto, A.; Markosyan, N.; Tyurin, V.A.; Tyurina, Y.Y.; Kar, G.; Fu, S.; Sehgal, M.; Garcia-Gerique, L.; Kossenkov, A.; et al. Ferroptosis of tumor neutrophils causes immune suppression in cancer. Nature 2022, 612, 338–346. [Google Scholar] [CrossRef]
  75. Zeng, W.; Zhang, R.; Huang, P.; Chen, M.; Chen, H.; Zeng, X.; Liu, J.; Zhang, J.; Huang, D.; Lao, L. Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer. Cancer Res. 2025, 85, 477–496. [Google Scholar] [CrossRef] [PubMed]
  76. Ma, L.; Chen, C.; Zhao, C.; Li, T.; Ma, L.; Jiang, J.; Duan, Z.; Si, Q.; Chuang, T.H.; Xiang, R.; et al. Targeting carnitine palmitoyl transferase 1A (CPT1A) induces ferroptosis and synergizes with immunotherapy in lung cancer. Signal Transduct. Target. Ther. 2024, 9, 64. [Google Scholar] [CrossRef]
  77. 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. [Google Scholar] [CrossRef]
  78. Lin, J.F.; Hu, P.S.; Wang, Y.Y.; Tan, Y.T.; Yu, K.; Liao, K.; Wu, Q.N.; Li, T.; Meng, Q.; Lin, J.Z.; et al. Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis. Signal Transduct. Target. Ther. 2022, 7, 54. [Google Scholar] [CrossRef]
  79. Chen, X.J.; Guo, C.H.; Yang, Y.; Wang, Z.C.; Liang, Y.Y.; Cai, Y.Q.; Cui, X.F.; Fan, L.S.; Wang, W. HPV16 integration regulates ferroptosis resistance via the c-Myc/miR-142-5p/HOXA5/SLC7A11 axis during cervical carcinogenesis. Cell Biosci. 2024, 14, 129. [Google Scholar] [CrossRef]
  80. Vokshi, B.H.; Davidson, G.; Tawanaie Pour Sedehi, N.; Helleux, A.; Rippinger, M.; Haller, A.R.; Gantzer, J.; Thouvenin, J.; Baltzinger, P.; Bouarich, R.; et al. SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. Nat. Commun. 2023, 14, 3034. [Google Scholar] [CrossRef]
  81. Alborzinia, H.; Flórez, A.F.; Kreth, S.; Brückner, L.M.; Yildiz, U.; Gartlgruber, M.; Odoni, D.I.; Poschet, G.; Garbowicz, K.; Shao, C.; et al. MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat. Cancer 2022, 3, 471–485. [Google Scholar] [CrossRef]
  82. Sun, N.; Wang, J.; Qin, J.; Ma, S.; Luan, J.; Hou, G.; Zhang, W.; Gao, M. Oncogenic RTKs sensitize cancer cells to ferroptosis via c-Myc mediated upregulation of ACSL4. Cell Death Dis. 2024, 15, 861. [Google Scholar] [CrossRef]
  83. Jiménez-Sánchez, A.; Cybulska, P.; Mager, K.L.; Koplev, S.; Cast, O.; Couturier, D.L.; Memon, D.; Selenica, P.; Nikolovski, I.; Mazaheri, Y.; et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat. Genet. 2020, 52, 582–593. [Google Scholar] [CrossRef]
  84. Teo, J.M.N.; Chen, Z.; Chen, W.; Tan, R.J.Y.; Cao, Q.; Chu, Y.; Ma, D.; Chen, L.; Yu, H.; Lam, K.H.; et al. Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma. J. Exp. Med. 2025, 222, e20241442. [Google Scholar] [CrossRef]
  85. Kortlever, R.M.; Sodir, N.M.; Wilson, C.H.; Burkhart, D.L.; Pellegrinet, L.; Brown Swigart, L.; Littlewood, T.D.; Evan, G.I. Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell 2017, 171, 1301–1315.e14. [Google Scholar] [CrossRef]
  86. Baird, A.M.; Leonard, J.; Naicker, K.M.; Kilmartin, L.; O’Byrne, K.J.; Gray, S.G. IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer. Lung Cancer 2013, 79, 83–90. [Google Scholar] [CrossRef]
  87. Teng, M.W.; Andrews, D.M.; McLaughlin, N.; von Scheidt, B.; Ngiow, S.F.; Möller, A.; Hill, G.R.; Iwakura, Y.; Oft, M.; Smyth, M.J. IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proc. Natl. Acad. Sci. USA 2010, 107, 8328–8333. [Google Scholar] [CrossRef]
  88. Sorrentino, C.; Ciummo, S.L.; D’Antonio, L.; Fieni, C.; Lanuti, P.; Turdo, A.; Todaro, M.; Di Carlo, E. Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome. J. Immunother. Cancer 2021, 9, e002966. [Google Scholar] [CrossRef]
  89. Cho, K.M.; Kim, M.S.; Jung, H.J.; Choi, E.J.; Kim, T.S. Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway. Front. Immunol. 2019, 10, 2142. [Google Scholar] [CrossRef]
  90. Zhao, P.; Sun, X.; Li, H.; Liu, Y.; Cui, Y.; Tian, L.; Cheng, Y. c-Myc Targets HDAC3 to Suppress NKG2DL Expression and Innate Immune Response in N-Type SCLC through Histone Deacetylation. Cancers 2022, 14, 457. [Google Scholar] [CrossRef]
  91. Lam, A.R.; Bert, N.L.; Ho, S.S.; Shen, Y.J.; Tang, L.F.; Xiong, G.M.; Croxford, J.L.; Koo, C.X.; Ishii, K.J.; Akira, S.; et al. RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer Res. 2014, 74, 2193–2203. [Google Scholar] [CrossRef]
  92. Muthalagu, N.; Monteverde, T.; Raffo-Iraolagoitia, X.; Wiesheu, R.; Whyte, D.; Hedley, A.; Laing, S.; Kruspig, B.; Upstill-Goddard, R.; Shaw, R.; 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 Discov. 2020, 10, 872–887. [Google Scholar] [CrossRef]
  93. Maeda, T.; Hiraki, M.; Jin, C.; Rajabi, H.; Tagde, A.; Alam, M.; Bouillez, A.; Hu, X.; Suzuki, Y.; Miyo, M.; et al. MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Res. 2018, 78, 205–215. [Google Scholar] [CrossRef]
  94. Xu, Y.; Poggio, M.; Jin, H.Y.; Shi, Z.; Forester, C.M.; Wang, Y.; Stumpf, C.R.; Xue, L.; Devericks, E.; So, L.; et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat. Med. 2019, 25, 301–311. [Google Scholar] [CrossRef]
  95. Vartuli, R.L.; Zhou, H.; Zhang, L.; Powers, R.K.; Klarquist, J.; Rudra, P.; Vincent, M.Y.; Ghosh, D.; Costello, J.C.; Kedl, R.M.; et al. Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation. J. Clin. Investig. 2018, 128, 2535–2550. [Google Scholar] [CrossRef]
  96. Good, C.R.; Aznar, M.A.; Kuramitsu, S.; Samareh, P.; Agarwal, S.; Donahue, G.; Ishiyama, K.; Wellhausen, N.; Rennels, A.K.; Ma, Y.; et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 2021, 184, 6081–6100.e26. [Google Scholar] [CrossRef]
  97. Kim, M.; Singh, M.; Lee, B.K.; Hibbs, M.; Richardson, K.; Ellies, L.; Wintle, L.; Stuart, L.M.; Wang, J.Y.; Voon, D.C.; et al. A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer. Oncogenesis 2022, 11, 60. [Google Scholar] [CrossRef]
  98. Dong, H.; Hu, J.; Wang, L.; Qi, M.; Lu, N.; Tan, X.; Yang, M.; Bai, X.; Zhan, X.; Han, B. SOX4 is activated by C-MYC in prostate cancer. Med. Oncol. 2019, 36, 92. [Google Scholar] [CrossRef]
  99. Marin, D.; Li, Y.; Basar, R.; Rafei, H.; Daher, M.; Dou, J.; Mohanty, V.; Dede, M.; Nieto, Y.; Uprety, N.; et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B-cell tumors: A phase 1/2 trial. Nat. Med. 2024, 30, 772–784. [Google Scholar] [CrossRef]
  100. Luo, J.; Guo, M.; Huang, M.; Liu, Y.; Qian, Y.; Liu, Q.; Cao, X. Neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via c-Myc/NRF1 activation. Signal Transduct. Target. Ther. 2025, 10, 78. [Google Scholar] [CrossRef]
  101. Daher, M.; Basar, R.; Gokdemir, E.; Baran, N.; Uprety, N.; Nunez Cortes, A.K.; Mendt, M.; Kerbauy, L.N.; Banerjee, P.P.; Shanley, M.; et al. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood 2021, 137, 624–636. [Google Scholar] [CrossRef]
  102. Dong, H.; Adams, N.M.; Xu, Y.; Cao, J.; Allan, D.S.J.; Carlyle, J.R.; Chen, X.; Sun, J.C.; Glimcher, L.H. The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nat. Immunol. 2019, 20, 865–878. [Google Scholar] [CrossRef]
  103. Schuler, M.; Cuppens, K.; Plönes, T.; Wiesweg, M.; Du Pont, B.; Hegedus, B.; Köster, J.; Mairinger, F.; Darwiche, K.; Paschen, A.; et al. Neoadjuvant nivolumab with or without relatlimab in resectable non-small cell lung cancer: A randomized phase 2 trial. Nat. Med. 2024, 30, 1602–1611. [Google Scholar] [CrossRef]
  104. Psyrri, A.; Fayette, J.; Harrington, K.; Gillison, M.; Ahn, M.J.; Takahashi, S.; Weiss, J.; Machiels, J.P.; Baxi, S.; Vasilyev, A.; et al. Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study. Ann. Oncol. 2023, 34, 262–274. [Google Scholar] [CrossRef]
  105. Cheng, W.; Kang, K.; Zhao, A.; Wu, Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J. Hematol. Oncol. 2024, 17, 54. [Google Scholar] [CrossRef]
  106. Xu, D.; Wang, H.; Bao, Q.; Jin, K.; Liu, M.; Liu, W.; Yan, X.; Wang, L.; Zhang, Y.; Wang, G.; et al. The anti-PD-L1/CTLA-4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: A phase II trial. Nat. Commun. 2025, 16, 1443. [Google Scholar] [CrossRef]
  107. Li, Q.; Liu, J.; Zhang, Q.; Ouyang, Q.; Zhang, Y.; Liu, Q.; Sun, T.; Ye, F.; Zhang, B.; Xia, S.; et al. The anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in first-line treatment of metastatic triple-negative breast cancer: A multicenter phase II trial. Nat. Commun. 2024, 15, 1015. [Google Scholar] [CrossRef]
  108. Galle, P.; Finn, R.S.; Mitchell, C.R.; Ndirangu, K.; Ramji, Z.; Redhead, G.S.; Pinato, D.J. Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: A systematic review. J. Immunother. Cancer 2024, 12, e008266. [Google Scholar] [CrossRef]
  109. Fan, Y.; Song, S.; Li, Y.; Dhar, S.S.; Jin, J.; Yoshimura, K.; Yao, X.; Wang, R.; Scott, A.W.; Pizzi, M.P.; et al. Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases. Cancer Res. 2023, 83, 3726–3738. [Google Scholar] [CrossRef]
  110. Gimple, R.C.; Yang, K.; Halbert, M.E.; Agnihotri, S.; Rich, J.N. Brain cancer stem cells: Resilience through adaptive plasticity and hierarchical heterogeneity. Nat. Rev. Cancer 2022, 22, 497–514. [Google Scholar] [CrossRef]
  111. Wang, W.; Zou, W. Amino Acids and Their Transporters in T-Cell Immunity and Cancer Therapy. Mol. Cell 2020, 80, 384–395. [Google Scholar] [CrossRef] [PubMed]
  112. Yuan, H.; Wu, X.; Wu, Q.; Chatoff, A.; Megill, E.; Gao, J.; Huang, T.; Duan, T.; Yang, K.; Jin, C.; et al. Lysine catabolism reprograms tumor immunity through histone crotonylation. Nature 2023, 617, 818–826. [Google Scholar] [CrossRef]
  113. Cao, T.; Zhang, W.; Wang, Q.; Wang, C.; Ma, W.; Zhang, C.; Ge, M.; Tian, M.; Yu, J.; Jiao, A.; et al. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells. Cell 2024, 187, 2288–2304.e27. [Google Scholar] [CrossRef] [PubMed]
  114. Tang, X.; Guo, Y.; Zhang, S.; Wang, X.; Teng, Y.; Jin, Q.; Jin, Q.; Shen, W.; Wang, R. Solanine Represses Gastric Cancer Growth by Mediating Autophagy Through AAMDC/MYC/ATF4/Sesn2 Signaling Pathway. Drug Des. Dev. Ther. 2023, 17, 389–402. [Google Scholar] [CrossRef]
  115. Calhoon, D.; Sang, L.; Ji, F.; Bezwada, D.; Hsu, S.C.; Cai, F.; Kim, N.; Basu, A.; Wu, R.; Pimentel, A.; et al. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis. Nature 2025. ahead of print. [Google Scholar] [CrossRef] [PubMed]
  116. Omodei, M.S.; Chimicoviaki, J.; Buttros, D.A.B.; Almeida-Filho, B.S.; Carvalho-Pessoa, C.P.; Carvalho-Pessoa, E.; Vespoli, H.L.; Nahas, E.A.P. Vitamin D Supplementation Improves Pathological Complete Response in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy: A Randomized Clinical Trial. Nutr. Cancer 2025, 77, 648–657. [Google Scholar] [CrossRef]
  117. Whitfield, J.R.; Soucek, L. MYC in cancer: From undruggable target to clinical trials. Nat. Rev. Drug Discov. 2025, 24, 445–457. [Google Scholar] [CrossRef]
  118. Boyd, S.R.; Chamakuri, S.; Trostle, A.J.; Chen, H.; Liu, Z.; Jian, A.; Wang, J.; Malovannaya, A.; Young, D.W. MYC-Targeting PROTACs Lead to Bimodal Degradation and N-Terminal Truncation. ACS Chem. Biol. 2025, 20, 896–906. [Google Scholar] [CrossRef]
  119. Ma, J.; Li, L.; Ma, B.; Liu, T.; Wang, Z.; Ye, Q.; Peng, Y.; Wang, B.; Chen, Y.; Xu, S.; et al. MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation. Nat. Commun. 2024, 15, 1871. [Google Scholar] [CrossRef]
  120. Weber, L.I.; Hartl, M. Strategies to target the cancer driver MYC in tumor cells. Front. Oncol. 2023, 13, 1142111. [Google Scholar] [CrossRef] [PubMed]
  121. Jeong, K.C.; Ahn, K.O.; Yang, C.H. Small-molecule inhibitors of c-Myc transcriptional factor suppress proliferation and induce apoptosis of promyelocytic leukemia cell via cell cycle arrest. Mol. Biosyst. 2010, 6, 1503–1509. [Google Scholar] [CrossRef]
  122. Carabet, L.A.; Lallous, N.; Leblanc, E.; Ban, F.; Morin, H.; Lawn, S.; Ghaidi, F.; Lee, J.; Mills, I.G.; Gleave, M.E.; et al. Computer-aided drug discovery of Myc-Max inhibitors as potential therapeutics for prostate cancer. Eur. J. Med. Chem. 2018, 160, 108–119. [Google Scholar] [CrossRef]
  123. Guo, J.; Parise, R.A.; Joseph, E.; Egorin, M.J.; Lazo, J.S.; Prochownik, E.V.; Eiseman, J.L. Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc-Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice. Cancer Chemother. Pharmacol. 2009, 63, 615–625. [Google Scholar] [CrossRef] [PubMed]
  124. Lu, X.; Vogt, P.K.; Boger, D.L.; Lunec, J. Disruption of the MYC transcriptional function by a small-molecule antagonist of MYC/MAX dimerization. Oncol. Rep. 2008, 19, 825–830. [Google Scholar] [CrossRef] [PubMed]
  125. Yap, J.L.; Wang, H.; Hu, A.; Chauhan, J.; Jung, K.Y.; Gharavi, R.B.; Prochownik, E.V.; Fletcher, S. Pharmacophore identification of c-Myc inhibitor 10074-G5. Bioorg. Med. Chem. Lett. 2013, 23, 370–374. [Google Scholar] [CrossRef] [PubMed]
  126. Castell, A.; Yan, Q.; Fawkner, K.; Hydbring, P.; Zhang, F.; Verschut, V.; Franco, M.; Zakaria, S.M.; Bazzar, W.; Goodwin, J.; et al. A selective high affinity MYC-binding compound inhibits MYC:MAX interaction and MYC-dependent tumor cell proliferation. Sci. Rep. 2018, 8, 10064. [Google Scholar] [CrossRef]
  127. Draeger, L.J.; Mullen, G.P. Interaction of the bHLH-zip domain of c-Myc with H1-type peptides. Characterization of helicity in the H1 peptides by NMR. J. Biol. Chem. 1994, 269, 1785–1793. [Google Scholar] [CrossRef] [PubMed]
  128. Soodgupta, D.; Pan, D.; Cui, G.; Senpan, A.; Yang, X.; Lu, L.; Weilbaecher, K.N.; Prochownik, E.V.; Lanza, G.M.; Tomasson, M.H. Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma. Mol. Cancer Ther. 2015, 14, 1286–1294. [Google Scholar] [CrossRef]
  129. Hart, J.R.; Garner, A.L.; Yu, J.; Ito, Y.; Sun, M.; Ueno, L.; Rhee, J.K.; Baksh, M.M.; Stefan, E.; Hartl, M.; et al. Inhibitor of MYC identified in a Kröhnke pyridine library. Proc. Natl. Acad. Sci. USA 2014, 111, 12556–12561. [Google Scholar] [CrossRef]
  130. Stellas, D.; Szabolcs, M.; Koul, S.; Li, Z.; Polyzos, A.; Anagnostopoulos, C.; Cournia, Z.; Tamvakopoulos, C.; Klinakis, A.; Efstratiadis, A. Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer. J. Natl. Cancer Inst. 2014, 106, dju320. [Google Scholar] [CrossRef]
  131. Lustig, L.C.; Dingar, D.; Tu, W.B.; Lourenco, C.; Kalkat, M.; Inamoto, I.; Ponzielli, R.; Chan, W.C.W.; Shin, J.A.; Penn, L.Z. Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth. Oncogene 2017, 36, 6830–6837. [Google Scholar] [CrossRef]
  132. Zeng, H.; Yang, H.; Song, Y.; Fang, D.; Chen, L.; Zhao, Z.; Wang, C.; Xie, S. Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma. Cell Death Dis. 2021, 12, 1048. [Google Scholar] [CrossRef] [PubMed]
  133. Cidado, J.; Boiko, S.; Proia, T.; Ferguson, D.; Criscione, S.W.; San Martin, M.; Pop-Damkov, P.; Su, N.; Roamio Franklin, V.N.; Sekhar Reddy Chilamakuri, C.; et al. AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells. Clin. Cancer Res. 2020, 26, 922–934. [Google Scholar] [CrossRef]
  134. Wang, X.; Yu, B.; Cao, B.; Zhou, J.; Deng, Y.; Wang, Z.; Jin, G. A chemical conjugation of JQ-1 and a TLR7 agonist induces tumoricidal effects in a murine model of melanoma via enhanced immunomodulation. Int. J. Cancer 2021, 148, 437–447. [Google Scholar] [CrossRef] [PubMed]
  135. Boss, D.S.; Witteveen, P.O.; van der Sar, J.; Lolkema, M.P.; Voest, E.E.; Stockman, P.K.; Ataman, O.; Wilson, D.; Das, S.; Schellens, J.H. Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann. Oncol. 2011, 22, 431–437. [Google Scholar] [CrossRef] [PubMed]
  136. Thomas, L.R.; Adams, C.M.; Wang, J.; Weissmiller, A.M.; Creighton, J.; Lorey, S.L.; Liu, Q.; Fesik, S.W.; Eischen, C.M.; Tansey, W.P. Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance. Proc. Natl. Acad. Sci. USA 2019, 116, 25260–25268. [Google Scholar] [CrossRef]
  137. Straining, R.; Eighmy, W. Tazemetostat: EZH2 Inhibitor. J. Adv. Pract. Oncol. 2022, 13, 158–163. [Google Scholar] [CrossRef]
  138. Wasko, U.N.; Jiang, J.; Dalton, T.C.; Curiel-Garcia, A.; Edwards, A.C.; Wang, Y.; Lee, B.; Orlen, M.; Tian, S.; Stalnecker, C.A.; et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature 2024, 629, 927–936. [Google Scholar] [CrossRef]
Pharmaceuticals 18 00978 g001
Figure 1. The MYC protein structure includes an (A) intrinsically disordered region as predicted by the (Predictor of Natural Disordered Regions (PONDR) (https://www.pondr.com/), accessed on 1 January 2025) alongside the (B) organization and conservation of its primary domains. (C) Prediction of intrinsically disordered regions in MYCN using the PONDR tool. (D) Structure of the primary protein domains and N-MYC conservation. (E) Prediction of intrinsically disordered regions in MYCL using the PONDR tool. (F) Structure of the primary protein domains and preservation of MYCL. The thickened straight lines represent the conservative areas.
Figure 1. The MYC protein structure includes an (A) intrinsically disordered region as predicted by the (Predictor of Natural Disordered Regions (PONDR) (https://www.pondr.com/), accessed on 1 January 2025) alongside the (B) organization and conservation of its primary domains. (C) Prediction of intrinsically disordered regions in MYCN using the PONDR tool. (D) Structure of the primary protein domains and N-MYC conservation. (E) Prediction of intrinsically disordered regions in MYCL using the PONDR tool. (F) Structure of the primary protein domains and preservation of MYCL. The thickened straight lines represent the conservative areas.
Pharmaceuticals 18 00978 g001
Pharmaceuticals 18 00978 g002
Figure 2. Cancer cells express high levels of the MYC protein through multiple mechanisms. Elevated levels of the MYC protein regulate various biological processes by extensively regulating the transcription of the genome.
Figure 2. Cancer cells express high levels of the MYC protein through multiple mechanisms. Elevated levels of the MYC protein regulate various biological processes by extensively regulating the transcription of the genome.
Pharmaceuticals 18 00978 g002
Pharmaceuticals 18 00978 g003
Figure 3. In cancer cells, MYC upregulates ASS1 expression, enhancing arginine biosynthesis and elevating its levels in the TME. This process effectively suppresses the antitumor function of CD8+ T cells, outweighing any potential arginine-mediated enhancement of their cytotoxic activity. Mechanistically, arginine is metabolized into polyamines within TAMs, which then promote their protumor polarization through TDG (thymine DNA glycosylase)-dependent DNA demethylation—a pathway modulated by p53 signaling. Arrows denote upregulation or an increase in expression levels, whereas other types of indicator lines represent inhibition.
Figure 3. In cancer cells, MYC upregulates ASS1 expression, enhancing arginine biosynthesis and elevating its levels in the TME. This process effectively suppresses the antitumor function of CD8+ T cells, outweighing any potential arginine-mediated enhancement of their cytotoxic activity. Mechanistically, arginine is metabolized into polyamines within TAMs, which then promote their protumor polarization through TDG (thymine DNA glycosylase)-dependent DNA demethylation—a pathway modulated by p53 signaling. Arrows denote upregulation or an increase in expression levels, whereas other types of indicator lines represent inhibition.
Pharmaceuticals 18 00978 g003
Pharmaceuticals 18 00978 g004
Figure 4. The impact of MYC on the tumor immune microenvironment and potential combinatory treatment strategies. The red arrow signifies the necessity of enhancing the process, while the four-leaf clover symbolizes the inhibition of the process. Of note, the red arrow points to the neutrophil, indicating an increased level of ferroptosis in this cell type.
Figure 4. The impact of MYC on the tumor immune microenvironment and potential combinatory treatment strategies. The red arrow signifies the necessity of enhancing the process, while the four-leaf clover symbolizes the inhibition of the process. Of note, the red arrow points to the neutrophil, indicating an increased level of ferroptosis in this cell type.
Pharmaceuticals 18 00978 g004
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Hong, Z.; Ming, S.; Luan, X.; Sun, Z.; Zhang, W. Beyond the Limit: MYC Mediates Tumor Immune Escape. Pharmaceuticals 2025, 18, 978. https://doi.org/10.3390/ph18070978

AMA Style

Hong Z, Ming S, Luan X, Sun Z, Zhang W. Beyond the Limit: MYC Mediates Tumor Immune Escape. Pharmaceuticals. 2025; 18(7):978. https://doi.org/10.3390/ph18070978

Chicago/Turabian Style

Hong, Zhongyang, Sitong Ming, Xin Luan, Zhe Sun, and Weidong Zhang. 2025. "Beyond the Limit: MYC Mediates Tumor Immune Escape" Pharmaceuticals 18, no. 7: 978. https://doi.org/10.3390/ph18070978

APA Style

Hong, Z., Ming, S., Luan, X., Sun, Z., & Zhang, W. (2025). Beyond the Limit: MYC Mediates Tumor Immune Escape. Pharmaceuticals, 18(7), 978. https://doi.org/10.3390/ph18070978

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop