Mechanisms of Cholangiocarcinoma, Molecular Subtypes, and Emerging Therapeutic Strategies

Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium and is characterized by an insidious onset, aggressive biological behavior, and poor overall prognosis. With the widespread application of high-throughput sequencing and multi-omics technologies, the molecular pathogenesis and classification of CCA have been progressively elucidated. Accumulating evidence suggests that genetic alterations, epigenetic reprogramming, a chronic inflammation-driven tumor microenvironment, and dysregulated immune surveillance collectively contribute to CCA initiation and progression. Moreover, CCAs originating from distinct anatomical sites and histological subtypes exhibit substantial differences in molecular features, clinical behavior, and therapeutic responsiveness. This review systematically summarizes current knowledge on the molecular mechanisms underlying CCA, delineates major molecular subtypes, and highlights recent advances in clinical management, with particular emphasis on targeted therapies and immunotherapies. In addition, molecular biomarkers associated with prognosis are discussed, aiming to provide a theoretical framework for molecular stratification, prognostic assessment, and biomarker-guided individualized treatment strategies in CCA.