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

Macrophage polarization of tumor-associated macrophages (TAMs) is critical for cancer development, while the impact of N-methyladenosine (mA) on the polarization of TAMs remains poorly understood. This study investigated the function of mA 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 mA-dependent manner, thereby inhibiting M2 polarization of TAMs. The mA binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) recognized the 3'-untranslated region (3'-UTR) mA 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 mA by the dmACRISPR 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 mA in macrophages was inversely proportional to the degree of macrophage infiltration in tumors. Collectively, mA suppressed M2 polarization of TAMs via Snail protein translation, which attenuated cancer cell growth and cancer development.