MA Regulator-based Methylation Modification Patterns Characterized by Distinct Tumor Microenvironment Immune Profiles in Colon Cancer

Recent studies have highlighted the biological significance of RNA N-methyladenosine (mA) modification in tumorigenicity and progression. However, it remains unclear whether mA modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. : In this study, we curated 23 mA regulators and performed consensus molecular subtyping with NMF algorithm to determine mA modification patterns and the mA-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based mSig scoring scheme was used to evaluate the mA modification patterns of individual tumors with an immune response. : Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified mA patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the mSig score, which was extracted from the mA-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower mSig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower mSig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., and ). In addition, patients with lower mSig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. : This study highlights that mA modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the mA modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.