2. Academic Validation
  3. N6-methyladenosine attenuates tumor-associated macrophages M2 polarization via suppressing the translation of Snail

N6-methyladenosine attenuates tumor-associated macrophages M2 polarization via suppressing the translation of Snail

  • Sci China Life Sci. 2025 Aug 21. doi: 10.1007/s11427-024-2897-y.
Yifan Tian # 1,  Jianxin Peng # 2,  Jiawang Zhou 1,  Weifeng Yang 3,  Yanxi Peng 4,  Jianing Li 1,  Yalan Rui 1,  Haisheng Zhang 1,  Guoyou Xie 1,  Haoran Wang 1,  Jiamin Wang 2,  Jiexin Li 1,  Zhiying Huang 1,  Xiaofan Ma 5,  Hongsheng Wang 6,  Junming He 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery; State Key Laboratory of Anti-Infective Drug Discovery and Development; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 Department of Hepatobiliary Surgery, Guangdong Province Traditional Chinese Medical Hospital, Guangzhou, 510120, China.
  • 3 Department of Colorectal Surgery, the Second Affiliated Hospital, South China University of Technology, Guangzhou, 510180, China.
  • 4 School of Public Health, Xiangnan University, Chenzhou, 423000, China.
  • 5 Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. maxf8@mail.sysu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery; State Key Laboratory of Anti-Infective Drug Discovery and Development; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. whongsh@mail.sysu.edu.cn.
  • 7 Department of Hepatobiliary Surgery, Guangdong Province Traditional Chinese Medical Hospital, Guangzhou, 510120, China. hejunming0101@sina.com.
  • # Contributed equally.
PMID: 40856928 DOI: 10.1007/s11427-024-2897-y
Abstract

Macrophage polarization of tumor-associated macrophages (TAMs) is critical for Cancer development, while the impact of N6-methyladenosine (m6A) on the polarization of TAMs remains poorly understood. This study investigated the function of m6A modification in macrophages and demonstrated that methyltransferase-like 3 (METTL3) can downregulate the alternatively activated macrophages (M2) polarization level of TAMs via suppression of snail family transcriptional repressor 1 (Snail) protein translation. Independent of protein stability, METTL3 restrained the translation efficiency of Snail in an m6A-dependent manner, thereby inhibiting M2 polarization of TAMs. The m6A binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) recognized the 3'-untranslated region (3'-UTR) m6A modification site of Snail and regulated the translation of Snail through its influence on the binding of eukaryotic translation release factor 1 (eRF1) and eukaryotic translation release factor 3 (eRF3) to Snail mRNA. Targeted specific demethylation of Snail m6A by the dm6ACRISPR system can significantly increase the protein expression of Snail and M2 polarization of TAMs. In a mouse xenograft model, knocking down the expression of METTL3 in macrophages significantly promoted tumor growth. Meanwhile, database analyses indicated the level of m6A in macrophages was inversely proportional to the degree of macrophage infiltration in tumors. Collectively, m6A suppressed M2 polarization of TAMs via Snail protein translation, which attenuated Cancer cell growth and Cancer development.

Keywords

METTL3; Snail; TAMs; m6A; translation.

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