Methyltransferase-like 3: structure, biological function and role in tumor immune escape and treatment

Tumor immune escape (TIE) is a critical factor in tumorigenesis. As the most prevalent RNA modification in eukaryotes, N 6 -methyladenosine (m6A) is dynamically regulated and participates in the remodeling the tumor immune microenvironment. Methyltransferase-like 3 (METTL3), the core catalytic subunit of the m6A methyltransferase complex, exerts pivotal regulatory functions in this process. Accumulating evidence indicates that METTL3 modulates gene expression at the post-transcriptional level, contributing to TIE and significantly influencing the efficacy of tumor immunotherapy. In malignancies such as acute myelogenous leukemia, pancreatic cancer, and colorectal cancer, METTL3 drives both intrinsic metabolic reprogramming in tumor cells and functional phenotypic remodeling of tumor-infiltrating immune cells, thereby reshaping anti-tumor immune responses through dual pathways. However, the complete molecular network underlying METTL3-mediated TIE remains to be systematically elucidated. This review summarizes the molecular structure, biological functions, regulatory mechanisms of expression, and molecular regulatory networks of METTL3. It comprehensively elaborates on its mechanisms of action in TIE, focusing on tumor cell metabolic reprogramming and immune cell functional regulation, and analyzes its clinical expression profiles and therapeutic relevance. Furthermore, we discuss key unresolved scientific questions in this field, aiming to facilitate an in-depth understanding of the specific mechanisms of METTL3 in tumorigenesis and to promote its clinical translational applications. In conclusion, as a critical molecular hub bridging intrinsic tumor cell properties and microenvironmental immune responses, METTL3 represents a highly promising anti-tumor therapeutic target. Nevertheless, translating precise targeting strategies into tangible clinical benefits depends on further refined dissection of the regulatory network within the TIE and the development of highly specific targeted agents.