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 MacroLYVE1, (ISMLYVE1) ): Stroma-rich with LYVE1+ macrophages and epithelial-mesenchymal transition (EMT) activation; C3 (Immune-Activated MacroC1QC (ISMC1QC) ): 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.
Chen et al. (Fri,) studied this question.