Recent studies have highlighted the biological significance of RNA N⁶-methyladenosine (m⁶A) modification in tumorigenicity and progression. However, it remains unclear whether m⁶A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods: In this study, we curated 23 m⁶A regulators and performed consensus molecular subtyping with NMF algorithm to determine m⁶A modification patterns and the m⁶A-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 m⁶Sig scoring scheme was used to evaluate the m⁶A modification patterns of individual tumors with an immune response. Results: 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 m⁶A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m⁶Sig score, which was extracted from the m⁶A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m⁶Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m⁶Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4). In addition, patients with lower m⁶Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. Conclusions: This study highlights that m⁶A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m⁶A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.

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