Cholangiocarcinoma — Novel Biological Insights and Therapeutic Strategies

Cholangiocarcinoma is a malignancy that continues to be associated with a dismal prognosis, and a better understanding of the disease biology is required to improve early detection and treatment strategies. In this Review, the authors describe key scientific and clinical advances made in this area over the past 5 years, encompassing novel insights into the tumour stroma and immune microenvironment, promising progress in developing liquid biopsy approaches for diagnosis and monitoring, clinical translation of molecularly targeted therapies, emerging immunotherapies and reassessment of the potential role of liver transplantation. In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.