Glycolysis induced by METTL14-related m6A methylation is essential for macrophage phagocytosis and phenotype in cervical cancer
N6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and it plays a vital role in various biological processes. However, the roles of m6A on cervical cancer tumorigenesis, especially macrophages infiltrated in the tumor microenvironment (TME) of cervical cancer, are still unclear. We analyzed the abnormal m6A methylation in cervical cancer, using CaSki and THP-1 cell lines, that might influence macrophages' polarization and/or function. In addition, C57bl-6j and Balb/c-nude mice were used for validation in vivo In this study, MeRIP-Seq analysis revealed the m6A profiles in cervical cancer. Then, we discovered the high expression of METTL14 (methyltransferase 14, N6-adenosine-methyltransferase subunit) in cervical cancer tissues can promote the proportion of PD-1 positive tumor-associated macrophages (TAMs), which have an obstacle to devour tumor cells. Functional, changes of METTL14 in cervical cancer inhibits the recognition and phagocytosis of macrophages to tumor cells. Mechanistically, the abnormality of METTL14 could target the glycolysis of tumor in vivo and vitro. Moreover, lactate acid produced by tumor glycolysis has an important role in the PD-1 expression of TAMs as a proinflammatory and immunosuppressive mediator. The study revealed the effect of glycolysis regulated by METTL14-related methylation on the expression of PD-1 and phagocytosis of macrophages, which showed that METTL14 was a potential therapeutic target for treating advanced human cancers. Overall design: To study the m6A methylation levels in cervical cancer and normal tissues.