Identification of cross-talk between m⁶A and 5mC regulators associated with onco-immunogenic features and prognosis across 33 cancer types

Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (m⁶A) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between m⁶A and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between m⁶A and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between m⁶A and 5mC methylation at the multiomic level. Then, we further established m⁶A/5mC epigenetic module eigengenes by combining hub m⁶A/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.