Harnessing cellular immunotherapy for cholangiocarcinoma: an integrated roadmap for overcoming resistance

The rising global incidence and dismal prognosis of cholangiocarcinoma (CCA) underscore the profound limitations of standard therapies. While chimeric antigen receptor (CAR)-based cellular immunotherapies represent a paradigm shift in oncology, their success in CCA is fundamentally constrained by a desmoplastic, immunosuppressive tumour microenvironment (TME) and significant tumour antigen heterogeneity. This review advances the thesis that overcoming these barriers requires an integrated approach combining multi-antigen, armoured CAR designs with rational adjuvant strategies (i.e combination therapy). We provide a comparative analysis of key tumour-associated antigens (TAAs)-including MUC1, c-MET, and the cancer stem cell marker CD133-evaluating their expression profiles, preclinical efficacy, and clinical status. The review further deconstructs the core mechanisms of therapeutic resistance in CCA-spanning physical, immunological, and metabolic barriers-and map them to next-generation engineering strategies designed to counteract them. In a novel synthesis, we explore the synergistic potential of combining CAR therapies with checkpoint inhibitors and immunomodulatory natural compounds. Critically appraising the current clinical trial landscape, we identify key weaknesses and propose strategic recommendations for biomarker-driven, adaptive trial designs. Finally, we present a forward-looking, four-pillar roadmap for future research, positioning the integration of advanced CAR engineering, multi-antigen platforms, synergistic adjuvants, and alternative effectors as the definitive research agenda for translating the promise of cellular immunotherapy into a clinical reality for CCA.