Abstract: Intrahepatic cholangiocarcinoma (ICC) is a rare, highly malignant, and heterogeneous group of primary hepatic adenocarcinomas that differs distinctly from conventional hepatocellular carcinoma. A specific cell population plays a crucial role in ICC named cancer-associated fibroblasts (CAFs). CAFs are involved in the connective tissue proliferative response in ICC, and this response manifests as a dense, fibrocollagen-rich tumor stroma. Thus, although chemotherapy and radiotherapy are the primary approaches to improve survival rates in patients with ICC, the presence of CAFs still render many patients refractory to these therapies. In this article, we explored the complex disease process of ICC in depth, reviewed the origin, heterogeneity, and function of CAFs, and focused on how CAFs subpopulations could be used as biomarkers and contribute to ICC treatment resistance. We also described current breakthroughs in targeting CAFs to overcome cancer treatment resistance and discussed emerging targeted therapies for CAFs. This article aims to provide a comprehensive overview of the latest advances and breakthrough directions in ICC treatment, hoping to offer new insights for future research and clinical practice. Keywords: cancer-associated fibroblasts, cancer therapy, drug resistance, intrahepatic cholangiocarcinoma, resistance mechanisms, tumor microenvironment
Yuan et al. (2026) studied this question.