N6-methyladenosine (m6A) RNA modification in tumor immunity

Abstract

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.

Keywords: N⁶-methyladenosine (m⁶A) modification; immune cells; immune evasion; tumor immunology; tumor microenvironment (TME).

Figure 1

Overview of RNA N⁶-methyladenosine (m⁶A) modification. The m⁶A modification is modulated by m⁶A “writers”, “erasers”, and “readers”. m⁶A “writers” are methylase complexes including METTL3, METTL14, ZC3H13, RBM15, VIRMA, HAKAI, WTAP, and METTL16. “Erasers” are demethylases (FTO, ALKHB5) that remove methyl groups. The m⁶A-containing RNAs are recognized by “readers”, which are involved in multiple processes of RNA metabolism, such as primary miRNA processing, alternative splicing, mRNA stabilization, translation, and degradation.

Figure 2

Key regulation of m⁶A modification in tumor immunity. As shown, the m⁶A modification is involved in anti-tumor immunity and tumor immune evasion. m⁶A methylation plays an essential role in the maintenance of immune cell homeostasis and function. Moreover, m⁶A modification patterns have an indispensable role in overall TME infiltration and the immune evasive phenotype. The close correlation between m⁶A-related risk signatures and the tumor immune microenvironment landscape supports the prognostic value and therapeutic efficacy of m⁶A regulators in a variety of cancer types.