Abstract
N6-methylation of adenosine (m6A), a post-transcriptional regulatory mechanism, is the most abundant nucleotide modification in almost all types of RNAs. The biological function of m6A in regulating the expression of oncogenes or tumor suppressor genes has been widely investigated in various cancers. However, recent studies have addressed a new role of m6A modification in the anti-tumor immune response. By modulating the fate of targeted RNA, m6A affects tumor-associated immune cell activation and infiltration in the tumor microenvironment (TME). In addition, m6A-targeting is found to affect the efficacy of classical immunotherapy, which makes m6A a potential target for immunotherapy. Although m6A modification together with its regulators may play the exact opposite role in different tumor types, targeting m6A regulators has been shown to have wide implications in several cancers. In this review, we discussed the link between m6A modification and tumor with an emphasis on the importance of m6A in anti-tumor immune response and immunotherapy.
Highlights
The expression of genetic information is regulated at multiple levels
We briefly introduce the regulation and function of m6A, with an emphasis on the role of m6A in anti-tumor immune response and a summary of prominent m6A-related functions and strategies in immunotherapy
Since there is no clinical research investigating the efficacy of m6A-targeting strategy, we propose several pathways we might utilize to implement m6A area of research in the clinical settings of treatment, which is usually done by trying to selectively identify and to inhibit the enzymes responsible for tumor exacerbation in specific cancers (Table 1)
Summary
The expression of genetic information is regulated at multiple levels. RNA modification, a posttranscriptional regulatory mechanism, is thought to alter the RNA function through changing the chemical-structural features of RNA [1]. M6A-related signature has been identified as biomarker for tumor immune phenotypes and anti-PD-1 immunotherapy treatment response in lung adenocarcinoma (LADC) [72, 73], stomach adenocarcinomas (STADs) [74], Esophageal squamous cell carcinoma (ESCC) [75, 76], Renal Papillary Cell Carcinoma (RPCC), Hepatocellular Carcinoma (HCC) [77, 78] These statistic results together indicate that m6A modification may reflect TME status and predict immunotherapy efficacy in pan-cancers instead of limited to specific cancer types. METTL3 and METTL14, as discussed earlier, play an oncogenic role and targeting them can lead to better clinical outcomes Examples of this include: [1] Depletion of the methyltransferases METLL3 in Tregs which enhances the antitumor ability of CD8+ T cells can be used as a strategy alongside immunotherapy for effective treatment [89]. Selective METTL3/METTL14 inhibitors for cancer therapies are not yet available, but bisubstrate inhibitors
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