METTL family proteins: functional heterogeneity, tumor regulatory networks, immune microenvironment remodeling and therapeutic potential

RNA methylation serves as an essential post-transcriptional epigenetic modification for gene expression regulation. The methyltransferase-like (METTL) family is characterized by conserved methyltransferase domains. These members can recognize multiple RNA substrates including messenger RNA (mRNA), ribosomal RNA (rRNA), and mitochondrial RNA (mtRNA), and engage in a variety of RNA methylation processes. They exhibit markedly heterogeneous tumor-regulatory functions. The METTL3/14 complex regulates tumor proliferation, metastasis, metabolic reprogramming and immunotherapy resistance by catalyzing mRNA N6-methyladenosine (m6A) modification. METTL5 targets rRNA and drives translational reprogramming to participate in tumor progression and T cell immune resistance. METTL17 mediates multiple methylations of mtRNA to deregulate mitochondrial metabolism and drive malignant tumor phenotypes. METTL16 possesses both mRNA m6A catalytic and small nuclear RNA non-catalytic functions, and participates in tumor progression and immune escape. METTL4 catalyzes N6, 2'-O-dimethyladenosine methylation to modulate target gene translation and facilitate tumorigenesis. Beyond RNA methylation, METTL7A/B promotes resistance to tumor-targeted drugs via m6A-independent mechanisms of DNA binding and protein interactions. Notably, the same METTL protein yields distinct immunoregulatory effects in tumor cells, T cells, macrophages and natural killer cells, with obvious context-dependence. In this paper, we systematically summarize structural features and functions of METTL family proteins, together with mechanisms underlying their regulation of the tumor immune microenvironment. We also consolidate the research progress and transformation bottlenecks of multiple targeted candidate molecules. It provides a theoretical basis and new ideas for further investigations of METTL-based tumor immunotargeted therapy.