Relationships of seven N6-methyladenosine regulators with the tumor microenvironment and tumor immune infiltrating cells

Abstract Background: N6-methyladenosine (m6A) modification plays key roles in tumor cell proliferation, invasion and immune escape, but the function of m6A modification in the tumor immune microenvironment and immunotherapy remain poorly understood.Methods: We researched the expression of seven m6A regulators (METTL3, WTAP, FTO, ALKBH5, ZC3H13, YTHDF1, YTHDF2) and their associations with prognosis using The Cancer Genome Atlas pan-cancer dataset. Further, we explored the relationships between expression of these m6A regulators and tumor mutation burden (TMB), microsatellite instability (MSI), stemness score, drug sensitivity, and immune subtype. Additionally, the association of these m6A regulators with the tumor microenvironment, immune-related gene expression, and tumor immune cell infiltration characteristics were systematically analyzed in pan-gynecological cancer. Results: The evaluated m6A regulators exhibited striking prognostic heterogeneity in the pan-cancer dataset. Moreover, expression levels of the m6A regulators were correlated with stemness score, MSI, and TMB in various types of cancer. METTL3, ZC3H13, FTO, and YTHDF1 were highly expressed in immune subtype C5 (immunologically quiet). In pan-gynecological cancers, m6A regulator expression was clearly correlated with stromal score, immune score, immune gene expression, and tumor immune infiltrating cells. Further, ZC3H13 expression was strongly correlated with tumor immune cell infiltration, and positively correlated with selumetinib, trametinib, hypothemycin, vemurafenib, dabrafenib, and cobimetinib drug sensitivity.Conclusions: In gynecological cancers, there are striking relationships between m6A regulator expression and the tumor microenvironment, immune genes, and tumor immune cell infiltration. These findings provide prospects for further investigation of m6A regulators as potential cancer therapeutic targets.