N6-Methyladenosine RNA Modification in the Tumor Immune Microenvironment: Novel Implications for Immunotherapy

Abstract

N6-methyladenosine (m6A) methylation is one of the most common modifications of RNA in eukaryotic cells, and is mainly regulated by m6A methyltransferases (writers), m6A demethylases (erasers), and m6A binding proteins (readers). Recently, accumulating evidence has shown that m6A methylation plays crucial roles in the regulation of the tumor immune microenvironment, greatly impacting the initiation, progression, and metastasis processes of various cancers. In this review we first briefly summarizes the m6A-related concepts and detection methods, and then describes in detail the associations of m6A methylation modification with various tumor immune components especially immune cells (e.g., regulatory T cells, dendritic cells, macrophages, and myeloid-derived suppressor cells) in a variety of cancers. We discuss the relationship between m6A methylation and cancer occurrence and development with the involvement of tumor immunity highlighted, suggesting novel markers and potential targets for molecular pathological diagnosis and immunotherapy of various cancers.

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…Specific depletion of METTL3 leads to impaired phenotypic and functional maturation of DCs and reduced expression of co-stimulatory molecules CD40, CD80 and cytokine IL-12 involved in maturation. Silencing of METTL3 has been shown to reduce the ability of DCs to stimulate T-cell responses [ 24 ]. Moreover, METTL3-mediated methylation of CD40, CD80 and TLR4 signal transduction junction TIRAP transcripts promotes translation in DCs to stimulate T-cell activation and enhances TLR4/NF-κB signaling to promote cytokine production [ 126 ].…”

“…To overcome these barriers, systematic evaluation of the phenotypic and functional changes of immune cells in TME is crucial. Interestingly, increasing evidence suggests that m 6 A methylation has the potential to support tumor immune escape via modulation of the immunosuppressive TME [ 22 – 24 ]. Indeed, tumor cell proliferation leads to hypoxia, which promotes the onset of metabolic reprogramming and participates in the phenotypic and functional conversion of immune cells in a m 6 A methylation-dependent manner, leading to the formation of an immunosuppressive tumor microenvironment (TME) that facilitates changes in mutually supportive biological functions to stimulate distant tumor metastasis.…”

Characterization of m6A Methylation Modification Patterns in Colorectal Cancer Determines Prognosis and Tumor Microenvironment Infiltration

“…Recent evidence has demonstrated that m6A modifications are involved in tumor immunity [ 22 ]. For the purpose of further analyzing the association between m6A modifications and the TME, we investigated the association of 21 m6A gene expression profiles with the infiltration of 22 distinct immune cell types.…”

“…Recent studies have linked m6A modifications to the regulation of tumor immunity and response to ICIs [ 22 ]. To date, accumulating reports have shown the crucial roles of m6A regulators in carcinogenesis, development, diagnosis, therapy, and prognosis [ 21 , 40 ].…”

“…Currently, numerous studies have offered evidence that m6A regulators perform crucial functions in modulating the maturation, translation, and degradation of RNAs (including mRNAs and noncoding RNAs). Cumulative studies have revealed that m6A regulator dysregulation is correlated with apoptosis, proliferation, self-renewal, developmental defects, malignant tumor progression, and tumor microenvironment (TME) [ 20 – 22 ]. TME refers to the environment surrounding tumor cells, including perivascular cells, immune cells, fibroblasts, molecules, extracellular matrix, and additional stromal components.…”