A Study of Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Jia Xiong et al
Description
[Unprocessed images of blots and gels, a single PDF is deposited as long as it is clear which figure and panel they correspond to] Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their immunosuppressive functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N6-methyladenosine (m6A) modification in controlling TIMs function is still poorly understood. Our study revealed that increased expression of RNA methyltransferase methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients and myeloid deficiency of METTL3 attenuated the tumor growth in mice. METTL3 mediates m6A modification of phosphokinase janus kinase 1 (Jak1) mRNA in TIMs and m6A-YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) axis enhances JAK1 protein translation efficiency in polysomes, which significantly contributes to the enhanced phosphorylation of the signal transducer and activator of transcription 3 (STAT3). Lactate accumulated in the tumor microenvironment is a key factor that induces the upregulation of METTL3 expression in TIMs via the form of histone H3K18 lactylation. Very interestingly, we also identified two lactylation modification sites in the Cys-Cys-Cys-His (CCCH) zinc finger domain of METTL3 and this type of lysine lactylation is essential for the target recognition domain of METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m6A modification for regulating the function of TIMs and provide new insights for the discovery of potential targets for cancer immunotherapy.