Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion. Importantly, recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition. N⁶-methyladenosine (m⁶A) modification, the most prevalent epigenetic modification of mammalian mRNAs, has essential functions in regulating the processing and metabolism of its targeted RNAs, and therefore affects various biological processes including tumorigenesis and progression. Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m⁶A modification in the regulation of tumor immunity. In this review, we summarize recent research progress in the potential roles of m⁶A modification in tumor immunoregulation, with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways. Furthermore, we review current knowledge regarding the close correlation between m⁶A-related risk signatures and the tumor immune microenvironment landscape, and we discuss the prognostic value and therapeutic efficacy of m⁶A regulators in a variety of cancer types.

The mRNA polyadenylation plays essential function in regulation of mRNA metabolism. Mis-regulations of mRNA polyadenylation are frequently linked with aberrant gene expression and disease progression. Under the action of polyadenylate polymerase, poly(A) tail is synthesized after the polyadenylation signal (PAS) sites on the mRNAs. Alternative polyadenylation (APA) often occurs in mRNAs with multiple poly(A) sites, producing different 3′ ends for transcript variants, and therefore plays important functions in gene expression regulation. In this review, we first summarize the classical process of mRNA 3′-terminal formation and discuss the length control mechanisms of poly(A) in nucleus and cytoplasm. Then we review the research progress on alternative polyadenylation regulation and the APA site selection mechanism. Finally, we summarize the functional roles of APA in the regulation of gene expression and diseases including cancers.

Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA m⁶A methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins. Functionally, we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development. Moreover, using Mettl5 knockout mouse model, we further demonstrated that Mettl5 knockout mice exhibit intellectual disability, recapitulating the human phenotype. Mechanistically, we found that Mettl5 maintains brain function and intelligence by regulating the myelination process. Our study uncovered the causal correlation between mis-regulated 18S rRNA m⁶A modification and neural function defects, supporting the important physiological functions of rRNA modifications in human diseases.