Current status of targeted and immunotherapy for tumors of the biliary system

Cancers of the biliary tract (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinomas along with gallbladder carcinomas, persist as clinically complex oncological entities characterized by constrained treatment modalities and unfavorable clinical outcomes. Contemporary genomic characterization has revealed druggable genomic aberrations such as IDH1/2 gene mutations, FGFR2 rearrangements, and HER2 amplification events, creating opportunities for precision interventions. Specifically, fibroblast growth factor receptor inhibitors (e.g., pemigatinib, infigratinib) and isocitrate dehydrogenase-1 inhibitors (e.g., ivosidenib) have exhibited statistically significant clinical benefits in molecularly defined patient subgroups, subsequently obtaining therapeutic indications from regulatory agencies. Regarding immunotherapeutic approaches, programmed death-1/programmed death-ligand 1 blockade agents demonstrate limited efficacy in single-agent applications, with objective response rates ranging from 10% to 20%. Current translational research prioritizes multimodal therapeutic approaches integrating immune checkpoint inhibitors with cytotoxic chemotherapy, angiogenesis inhibitors, or novel immunostimulatory agents to potentiate antitumor immune responses. Biomarkers like tumor mutational burden, microsatellite instability, and PD-L1 expression are being explored to predict therapeutic outcomes. Despite progress, challenges persist, including primary resistance mechanisms, tumor heterogeneity, and the need for improved preclinical models. This review synthesizes current evidence on targeted and immunotherapeutic approaches in BTCs, emphasizing the integration of precision medicine, biomarker-driven trials, and novel combination strategies to optimize clinical outcomes. Future research should focus on overcoming resistance, elucidating the tumor microenvironment's role, and expanding access to molecular testing to personalize treatment for this aggressive disease