Cholangiocarcinoma (CCA) is a highly aggressive malignancy of the biliary tract with limited therapeutic options and a dismal prognosis. Although immune checkpoint inhibitors (ICIs) have transformed treatment paradigms for several solid tumors, their impact on CCA remains minimal. The unique immunobiology of CCA, including its immune excluded phenotype, low tumor mutational burden, and paucity of actionable biomarkers, has constrained meaningful immunotherapy responses. This review outlines the key immunologic barriers that define the tumor microenvironment in CCA, including the abundance of myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, metabolic reprogramming, and immune checkpoint overexpression. Given the modest clinical outcomes of ICI monotherapy in CCA, we highlight the rationale for combination strategies incorporating chemotherapy, anti-angiogenic agents, epigenetic modulators, and metabolic inhibitors. Additionally, we assessed the emerging roles of adoptive cell therapy, tumor vaccines, and gut microbiome modulation as novel immunologic interventions. We also discussed how adaptive trial designs and real-time circulating tumor DNA monitoring support dynamic therapy optimization. Although the immunologic silence of CCA has historically limited the efficacy of immunotherapy, growing insights into the tumor microenvironment (TME) and advances in biomarker-guided, personalized strategies offer a compelling roadmap forward. Overcoming immune resistance in CCA will require multidimensional innovation combining biology, technology, and trial design to shift this malignancy from immune evasion to immune engagement.
Tang et al. (Thu,) studied this question.