Targeting MYC at the intersection between cancer metabolism and oncoimmunology

Abstract

MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets of cancer progression. Of interest, MYC governs oncometabolism through the interactions with its partners and cofactors, as well as cancer immunity via its gene targets. Recent investigations have taken interest in characterizing these interactions through multi-Omic approaches, to better understand the vastness of the MYC network. Of the several gene targets of MYC involved in either oncometabolism or oncoimmunology, few of them overlap in function. Prominent interactions have been observed with MYC and HIF-1α, in promoting glucose and glutamine metabolism and activation of antigen presentation on regulatory T cells, and its subsequent metabolic reprogramming. This review explores existing knowledge of the role of MYC in oncometabolism and oncoimmunology. It also unravels how MYC governs transcription and influences cellular metabolism to facilitate the induction of pro- or anti-tumoral immunity. Moreover, considering the significant roles MYC holds in cancer development, the present study discusses effective direct or indirect therapeutic strategies to combat MYC-driven cancer progression.

Keywords: MYC; cancer; immune evasion; metabolism; oncoimmunology.

Figure 1

AlphaFold predicted structure of MYC (AF- P01106-F1) its annotated structural domains and their respective interactors. LZ – Leucine Zipper, HLH – Helix-Loop-Helix, MB1-MB4 – MYC binding boxes. Created with BioRender.com.

Figure 2

Protein-protein interaction network analysis of MYC and its interacting partners reveal several key regulatory processes including cellular metabolism, immune system, cell cycle and cell death. FDR, false discovery rate.

Figure 3

The role of MYC-driven transcriptional activation on cancer and immune cell metabolism and its influence on anti-tumor immunity. Top-left panel shows CAF metabolic reprogramming as a result of activated MYC in tumors exporting miR-105 which is imported into CAFs and inhibits MXI1. Top-right panel shows the inactivation of CD8⁺ T cells by MYC activated export of PD-L1 from tumor cells bound to PD-1 receptors on CD8^+. T cells. Middle left panel shows how the acidification of the microenvironment triggers p38 and c-Jun signaling pathways in CD8⁺ T cells which promotes interferon-mediated inactivation of CD8⁺ T cell function. Middle right panel shows lactate released in the tumor microenvironment from tumor cells polarizes the differentiation of M1 macrophages to M2 macrophages. The bottom panel shows how MYC activated transcription of key enzymes promotes Warburg Effect within tumor cells. Created with BioRender.com.

Figure 4

Direct and indirect MYC-targeted therapeutic strategies. Therapeutic inhibitors are depicted as labeled red boxes. PC585 inhibits CDK9, JQ1 inhibits BRD4, and THZ-1 inhibits CDK4, which together are key transcription factors that regulate MYC gene expression. BEZ235 is a PI3K inhibitor, MK2206 is an Akt inhibitor, and Rapamycin is a mTOR inhibitor, which together inhibit the translation of MYC. 10074-G5, 10058-F4, Omomyc, and Mycro3 inhibits the heterodimerization of MYC and MAX. Entinostat inhibits HAT and 5’azacytidine inhibits DNMT which are co-factors that aid in MYC activated transcription of gene targets. FX11 inhibits LDHA, a gene target of MYC, and thus inhibits the downstream function of MYC activation. Created with BioRender.com.