How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration

Cholangiocarcinoma (CCA) consists of a class of malignant tumors of the biliary system, with a rising incidence and carries a poor prognosis. Developing reliable animal models of CCA is crucial to elucidate the pathogenesis, identify novel therapeutic targets, and assess treatment efficacy. Among these models, the in situ primary cholangiocarcinoma model which closely mimics clinical reality, serves as a robust tool for evaluating drug efficacy, simulating tumor progression characteristics, and facilitates immunotherapy strategies. Although in situ primary CCA models have been utilized in preclinical research, they have inherent limitations that warrant attention and further refinement. This review article highlights the status of the most relevant experimental animal models in preclinical CCA studies. It further delineates the differences in the development of intrahepatic and extrahepatic bile ducts that influence CCA model construction. In addition, we review the advancements, strengths and weaknesses of CCA organoids, primary intrahepatic and extrahepatic CCA models, and examine the pivotal role of bile duct inflammation and biliary fibrosis in creating the invasive cancer models. We emphasize the innovative application and immense potential of single-cell sequencing technology in studying cancer models. Additionally, this article summarizes the progress of CCA-targeted therapies and associated clinical trials which offered relevant insights. With a comprehensive review of in situ primary CCA models, we aim to provide suggestions and recommendation for future development of more advanced and clinically relevant research in constructing CCA models.