Links Between N⁶-Methyladenosine and Tumor Microenvironments in Colorectal Cancer

N-6-methyladenosine (m(6)A) 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 m(6)A "writers," "erasers," and "readers" in colorectal cancer and their association with TME characteristics. The m(6)A regulator genes showed specific patterns in co-mutation, copy number variation, and expression. Based on the transcriptomic data of the m(6)A regulators and their correlated genes, two types of subtyping systems, m(6)A(reg)Cluster and m(6)A(sig)Cluster, 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 m(6)Ascore 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 m(6)A modification and TME formation. Evaluating m(6)A in cancer has helped us comprehend the TME status, and targeting m(6)A in tumor cells might help modulate the TME and improve tumor therapy and immunotherapy.