The Role of m6A Modification in the PD-1/PD-L1 Pathway: from the Inherent Mechanism of Tumor Cells to the Regulation of Immune Microenvironment

Abstract

The most common epigenome modification in eukaryotic mRNA is N6-methyladenosine modification, which is often referred to as m6A modification. It plays an important role in carcinogenesis, immunological evasion, and drug resistance. The programmed cell death protein 1/programmed death ligand 1(PD-1/PD-L1) pathway is critical for tumor immune evasion. Targeting PD-1/PD-L1 pathway has emerged as a crucial method for treating patients who were diagnosed with advanced tumors. Recent studies have found that: (1) m6A modification acts on this pathway by regulating intrinsic mechanisms of tumor cells, such as affecting the expression of PD-L1 to make it enhanced or decreased or activating the downstream signaling pathway; (2) m6A modification regulates this pathway by modifying the immune environment such as influencing T cell activity and macrophage polarization; (3) m6A modification plays multiple roles in this pathway through the bidirectional regulatory network, suggesting its important clinical translational potential as a possible therapeutic target and prognosis indicator. This article systematically reviewed the mechanism of molecular action of m6A modification in this PD-1/PD-L1 pathway, explored its joint utility and potential intervention strategies, aiming to provide new ideas for overcoming immunotherapy resistance.