Abstract 7906: Integrated multi-omics profiling identifies an immunotherapy vulnerable and prognostic associated subtype in cholangiocarcinoma

Abstract 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. Citation Format: Lu Chen, Xiangdong Tian. Integrated multi-omics profiling identifies an immunotherapy vulnerable and prognostic associated subtype in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7906.