Links Between N ⁶-Methyladenosine and Tumor Microenvironments in Colorectal Cancer

N ⁶-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, m⁶A_regCluster and m⁶A_sigCluster, 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.