Immunotherapy and Targeted Therapy in Liver and Biliary Tract Cancer: Current Status and Latest Advancements

Hepatobiliary malignancies, comprising hepatocellular carcinoma (HCC) and biliary tract cancers (BTC), represent a growing global health burden with rising incidence linked to metabolic dysfunction-associated liver disease. Historically associated with poor prognosis and limited systemic options, these tumors have undergone a paradigm shift with the integration of immunotherapy and molecularly targeted strategies. This review provides a comprehensive overview of the evolving molecular landscape, tumour microenvironment, and therapeutic advances in advanced HCC and BTC, with emphasis on clinically relevant evidence and emerging research directions. HCC is characterized by marked genomic heterogeneity and an immunosuppressive tumour microenvironment that promotes immune evasion. Recent phase III trials have established combination regimens as the standard of care, including anti–PD-L1 plus anti-VEGF therapy and dual immune checkpoint blockade, both demonstrating significant survival benefit over tyrosine kinase inhibitor monotherapy. In BTC, the addition of immune checkpoint inhibitors to gemcitabine–cisplatin chemotherapy has redefined first-line treatment. Furthermore, advances in next-generation sequencing have enabled the identification of actionable genomic alterations in a substantial proportion of BTC patients, facilitating the use of targeted therapies directed against FGFR2, IDH1, HER2, BRAF, NTRK, and MSI-H/dMMR. Despite these advances, therapeutic resistance remains a major limitation, driven by tumour heterogeneity, immune exclusion, and T-cell exhaustion. The lack of robust predictive biomarkers further complicates treatment selection. Future research should prioritize biomarker-driven strategies, rational combination therapies, and integration of multi-omics and real-world data to advance precision oncology and improve clinical outcomes in hepatobiliary cancers.