The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications

Front Immunol. 2024 Jan 22:15:1335774. doi: 10.3389/fimmu.2024.1335774. eCollection 2024.

Abstract

The tumor microenvironment (TME) is a heterogeneous ecosystem comprising cancer cells, immune cells, stromal cells, and various non-cellular components, all of which play critical roles in controlling tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), the core component of N 6-methyladenosine (m6A) writer, is frequently associated with abnormalities in the m6A epitranscriptome in different cancer types, impacting both cancer cells and the surrounding TME. While the impact of METTL3 on cancer cells has been extensively reviewed, its roles in TME and anti-cancer immunity have not been comprehensively summarized. This review aims to systematically summarize the functions of METTL3 in TME, particularly its effects on tumor-infiltrating immune cells. We also elaborate on the underlying m6A-dependent mechanism. Additionally, we discuss ongoing endeavors towards developing METTL3 inhibitors, as well as the potential of targeting METTL3 to bolster the efficacy of immunotherapy.

Keywords: N6-methyladenosine (m6A); cancer immunotherapy; immune checkpoint inhibitors (ICI); methyltransferase-like 3 (METTL3); small molecular inhibitors; tumor-infiltrating immune cells (TICs).

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Methyltransferases* / genetics
  • Neoplasms* / genetics
  • RNA
  • Tumor Microenvironment*

Substances

  • Methyltransferases
  • RNA
  • METTL3 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by National Natural Science Foundation of China 82173058 (to HH), 82173289 (to WL), 82372986 (to WL) and 82304180 (to LC), Guangdong Basic and Applied Basic Research Foundation 2021A1515010425 (to HH), China Postdoctoral Science Foundation 2022M713585 (to LC), Young Talents Program of Sun Yat-sen University Cancer Center YTP-SYSUCC-0044 (to HH) and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University 23xkjc018 (to WL).