Links Between N6-Methyladenosine and Tumor Microenvironments in Colorectal Cancer

N6-methyladenosine (m6A) is a critical epigenetic modification for tumor malignancies, but its role in regulating the tumor microenvironments (TMEs) has not been fully studied. By integrating multiple data sets and multi-omics data, we comprehensively evaluated the m6A “writers,” “erasers,” and “readers” in colorectal cancer and their association with TME characteristics. The m6A regulator genes showed specific patterns in co-mutation, copy number variation, and expression. Based on the transcriptomic data of the m6A regulators and their correlated genes, two types of subtyping systems, m6AregCluster and m6AsigCluster, were developed. The clusters were distinct in pathways (metabolism/inflammation/extracellular matrix and interaction), immune phenotypes (immune-excluded/immune-inflamed/immune-suppressive), TME cell composition (lack immune and stromal cells/activated immune cells/stromal and immune-suppressive cells), stroma activities, and survival outcomes. We also established an m6Ascore associated with molecular subgroups, microsatellite instability, DNA repair status, mutation burdens, and survival and predicted immunotherapy outcomes. In conclusion, our work revealed a close association between m6A modification and TME formation. Evaluating m6A in cancer has helped us comprehend the TME status, and targeting m6A in tumor cells might help modulate the TME and improve tumor therapy and immunotherapy.