Integrative 5-Methylcytosine Modification Immunologically Reprograms Tumor Microenvironment Characterizations and...

The tumor microenvironment (TME) affects the biologic malignancy of clear cell renal cell carcinoma (ccRCC). The influence of the 5-methylcytosine (m⁵C) epigenetic modification on the TME is unknown. We comprehensively assessed m⁵C modification patterns of 860 ccRCC samples (training, testing, and real-world validation cohorts) based on 17 m⁵C regulators and systematically integrated the modification patterns with TME cell-infiltrating characterizations. Our results identified distinct m⁵C modification clusters with gradual levels of immune cell infiltration. The distinct m⁵C modification patterns differ in clinicopathological features, genetic heterogeneity, patient prognosis, and treatment responses of ccRCC. An elevated m⁵C score, characterized by malignant biologic processes of tumor cells and suppression of immunity response, implies an immune-desert TME phenotype and is associated with dismal prognosis of ccRCC. Activation of exhausted T cells and effective immune infiltration were observed in the low m⁵C score cluster, reflecting a noninflamed and immune-excluded TME phenotype with favorable survival and better responses to immunotherapy. Together, these findings provide insights into the regulation mechanisms of DNA m⁵C methylation modification patterns on the tumor immune microenvironment. Comprehensive assessment of tumor m⁵C modification patterns may enhance our understanding of TME cell-infiltrating characterizations and help establish precision immunotherapy strategies for individual ccRCC patients.