Correlated expression of MYBL2 and CCL5 defines an immunosuppressive microenvironment and predicts poor prognosis in intrahepatic cholangiocarcinoma

BACKGROUND: The tumor immune microenvironment critically influences progression and therapeutic response in intrahepatic cholangiocarcinoma (ICC). MYBL2 drives tumor aggressiveness, while CCL5 regulates immune-cell recruitment; however, their combined impact on immune composition and PD-1 therapy response remains undefined. METHODS: Tumor specimens from 127 ICC patients were assessed by immunohistochemistry and whole-slide digital quantification. MYBL2 and CCL5 expression were classified into four combinatorial phenotypes. Associations with immune-cell infiltration, survival, and treatment response were evaluated using correlation analysis, Kaplan-Meier curves, Cox regression, and PD-1 interaction analyses. Seventy patients received adjuvant PD-1 therapy. RESULTS: MYBL2 and CCL5 expression were positively correlated (r = 0.38, p < 0.001). Higher CCL5 levels were associated with increased CD163⁺ TAM density (r = 0.31, p < 0.001) and a reduced CD8/CD163 ratio, indicating an immunosuppressive microenvironment. The MYBL2-CCL5 classification provided clear prognostic discrimination, with the Double-High subgroup showing the shortest OS and PFS. Among PD-1-treated patients, treatment benefit varied markedly across phenotypes: the Double-Low group achieved the greatest survival advantage, whereas the Double-High group showed minimal response, reflecting primary resistance. In multivariable analysis, Double-Low remained strongly protective compared with Double-High. CONCLUSION: The MYBL2-CCL5 co-expression phenotype identifies an immunosuppressive, TAM-dominant microenvironment and serves as a dual biomarker for both prognosis and PD-1 treatment sensitivity in ICC. This immunologic classification offers a practical framework for postoperative risk stratification and personalized immunotherapy decision-making.