Molecular Mechanisms and Genetic Features of Cholangiocarcinoma: Implications for Targeted Therapeutic Strategies

Cholangiocarcinoma (CCA) is a biologically diverse and highly aggressive cancer that arises from the biliary epithelium. It is typically divided into intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) types, each with distinct clinical behavior, genetic alterations, and therapeutic responses. Worldwide, the global incidence of CCA has risen steadily, accounting for nearly 15% of liver cancers and about 3% of all gastrointestinal malignancies. CCA often presents at an advanced stage due to its silent onset and shows poor responsiveness to conventional chemotherapy, resulting in high mortality-approximately 2% of cancer-related deaths worldwide. Risk factors include parasitic infections like liver flukes and chronic biliary diseases such as cholelithiasis and primary sclerosing cholangitis, although most cases have unknown origins. While early-stage patients may benefit from surgical resection or liver transplantation, these options are often not viable in advanced disease due to high relapse rates. In cases of unresectable or metastatic CCA, treatment remains difficult due to resistance and a lack of effective targeted therapies. This review systematically integrates the genomic, epigenetic, and signaling network mechanisms underlying CCA with their translational implications, providing a critical synthesis of the rapidly evolving field of targeted therapies-including recently approved FDA treatments and emerging novel agents. We specifically emphasize the key mechanisms of therapeutic resistance and corresponding strategies to overcome them, present an updated evaluation of vulnerabilities across distinct molecular subgroups, and explore the major challenges and future trajectories for advancing biomarker-driven precision medicine in CCA, thereby offering a forward-looking and clinically relevant perspective.