The regulation and potential roles of m6A modifications in early embryonic development and immune tolerance at the maternal-fetal interface.

The immune microenvironment at the maternal-fetal interface was determined by the crosstalk between the trophoblast and maternal-derived cells, which dynamically changed during the whole gestation. Trophoblasts act as innate immune cells and dialogue with maternal-derived cells to ensure early embryonic development, depending on the local immune microenvironment. Therefore, dysfunctions in trophoblasts and maternal decidual cells contribute to pregnancy complications, especially recurrent pregnancy loss in early pregnancy. Since many unknown regulatory factors still affect the complex immune status, exploring new potential aspects that could influence early pregnancy is essential. RNA methylation plays an important role in contributing to the transcriptional regulation of various cells. Sufficient studies have shown the crucial roles of N6-methyladenosine (m6A)- and m6A-associated- regulators in embryogenesis during implantation. They are also essential in regulating innate and adaptive immune cells and the immune response and shaping the local and systemic immune microenvironment. However, the function of m6A modifications at the maternal-fetal interface still lacks wide research. This review highlights the critical functions of m6A in early embryonic development, summarizes the reported research on m6A in regulating immune cells and tumor immune microenvironment, and identifies the potential value of m6A modifications in shaping trophoblasts, decidual immune cells, and the microenvironment at the maternal-fetal interface. The m6A modifications are more likely to contribute to embryogenesis, placentation and shape the immune microenvironment at the maternal-fetal interface. Uncovering these crucial regulatory mechanisms could provide novel therapeutic targets for RNA methylation in early pregnancy.