Integrated multi-omics profiling identifies an immunotherapy vulnerable and prognostic associated subtype in cholangiocarcinoma

Cholangiocarcinoma (CCA) is an aggressive malignancy with poor prognosis and limited treatment options. This study performed integrated multi-omics profiling as well as immunohistochemical validation on 424 CCA patients, identifying four molecular subtypes with distinct clinical and immunological features: C1 (Proliferative): Driven by *TP53/KRAS* mutations and CpG island methylator phenotype (CIMP+) hypermethylation, showing Th17 cells infiltration and poor outcomes; C2 (Immune-Suppressed Macro_LYVE1, (ISM_LYVE1)): Stroma-rich with LYVE1⁺ macrophages and epithelial-mesenchymal transition (EMT) activation; C3 (Immune-Activated Macro_C1QC (ISM_C1QC)): Enriched in C1QC⁺ macrophages, CD8⁺ T-cells, and metabolic pathways, highly responsive to immune checkpoint blockade (75% Overall Response Rate (ORR)); C4 (Immune-Excluded, (IE)): FGFR2-altered and IDH1-mutant, with an immunologically-cold phenotype. We validated ATP2B1 as a novel prognostic biomarker and developed a 160-gene classifier for subtype prediction. The C3 subtype's exceptional immune checkpoint blockade (ICB) response, independent of conventional biomarkers (PD-L1/microsatellite instability (MSI)/tumor mutational burden (TMB)), highlights the clinical utility of this classification system in guiding precision immunotherapy for CCA.