MYC mutations are among the most common in human cancers and can not only cause cancer in normal cells but also help cancer cells escape the immune response. MYC protein, on the other hand, is a well-known "non-druggable" target, and no targeted drugs have yet been approved. Nature Reviews Clinical Oncology recently published a review of alternative ways for attacking it, entitled "The MYC oncogene—the grand orchestrator of cancer growth and immune evasion".

MYC protein overexpression occurs in 70-80% of all cancers. There are numerous mechanisms that lead to the activation of this signaling pathway, including mutations in the MYC gene that increase MYC expression or increased protein stability of MYC protein after translocation.

MYC, when overexpressed, has been demonstrated in studies to cause cancer in a variety of ways. Initially, it was thought to regulate the cell cycle and cell metabolism, facilitating rapid cell growth. Furthermore, scientists have recently revealed that the MYC protein can change the microenvironment of malignancies. It can, for example, influence endothelial cell and blood vessel proliferation, supplying more nutrients to malignancies.

More intriguingly, MYC proteins have been shown to influence the amounts of a range of immunological checkpoint proteins. MYC, for example, can increase the expression of the immunological checkpoint protein PD-L1, which limits immune cell function in the tumor microenvironment. Other studies have discovered that it can also upregulate CD47, which, when increased on the surface of cancer cells, can impede macrophage phagocytosis of cancer cells.

Because of the importance of MYC overexpression in tumor proliferation and immune evasion, inhibiting MYC activity has emerged as a key target in the development of anticancer treatments. MYC overexpression cancers become MYC-dependent, according to research. This suggests that inhibiting MYC activity can result in long-term tumor reduction. In a mouse model of lung cancer, expression of a dominant negative MYC mutant (OmoMYC) that inhibits MYC function causes tumor shrinking to occur quickly.

Furthermore, inhibiting MYC affects the tumor microenvironment and boosts the anti-cancer immune response. Animal investigations have revealed that innate immune cells (including macrophages and natural killer cells) and adaptive immunity effector cells (including CD4-positive T cells and B cells) are recruited to the tumor's vicinity within one week after reducing MYC activity.

Several MYC-targeting methods

MYC protein, on the other hand, is a transcription factor that forms a dimer with MAX protein and then binds to DNA to regulate gene expression. Not only does MYC lack the traditional active pocket, but it also lacks a consistent shape in some circumstances, making it challenging to target with small molecule drugs. However, in recent years, scientists have investigated various approaches to targeting MYC.

* Because MYC and MAX protein dimerization is required for their binding to DNA, inhibiting MYC-MAX protein binding can limit complex-mediated gene expression.
* From a genetic or mRNA standpoint, it is feasible to inhibit MYC protein expression and consequently its function.
* The advantage of this method is that the protein degrader does not need to bind to the active site of the target protein, but instead "pulls" it along with the E3 ubiquitin ligase. As a result, it is also an effective tool for targeting MYC, a "non-druggable" protein.
* Tumor cells become MYC-dependent in MYC-overexpressing malignancies. As a result, in patients with MYC gene amplification tumors, addressing targets downstream of MYC may be more effective.

MYC is a particularly intriguing target since it not only stimulates tumor cell proliferation but also modulates the host immune response. Over the last few years, researchers have made significant progress in understanding MYC-regulated tumor cell intrinsic processes, host immunological response, and vascular proliferation mechanisms, intended to enable developers to create novel MYC-targeting drugs.