Dynamic Responses of Cancer-Associated Fibroblasts to Therapy in Primary Liver Cancer

Cancer-associated fibroblasts (CAFs) are central players in the tumour microenvironment (TME) of primary liver cancer, influencing both cancer progression and treatment response. Studies involving single-cell RNA sequencing and spatial multi-omics have significantly expanded our understanding of CAF heterogeneity and functional diversity, although consolidated markers to identify CAF subtypes and therapy-dependent plasticity remain largely unknown. In this review, CAF subpopulations, including their markers and functions, are comprehensively summarised in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The spatial distribution of CAF subtypes from tumour core to boundary correlates with their phenotypes and functions. We focus on mapping dynamic changes of CAF subtypes in response to therapy, including chemotherapy and immunotherapy, and how these changes influence treatment response and prognosis in liver cancer. Finally, we discuss key challenges in targeting specific CAF subtypes and general CAF activation pathways in current clinical trials. This review provides a holistic view of the current and future landscape of CAF-targeting and CAF-regulating strategies in combination with standard-of-care treatments for liver cancer.