Pleiotropic mechanisms of cancer-associated fibroblast-mediated resistance in hepatocellular carcinoma: emerging therapeutic vulnerabilities and targeting strategies

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death around the world, with therapy resistance posing a substantial obstacle to enhancing patient outcomes. Cancer-associated fibroblasts (CAFs), the predominant stromal cells within the tumor microenvironment (TME), have been identified as pivotal contributors to HCC progression and therapeutic resistance. CAFs have direct or indirect interactions with cancer cells, leading to immune evasion and drug resistance. This review mostly concentrates on the role of CAFs in HCC, particularly how CAFs influence chemotherapy, targeted therapy, and immunotherapy. Additionally, it explores synergistic therapeutic strategies targeting CAFs. It has been found that targeting CAFs or disrupting their interactions with other cells offers promising avenues for dealing with drug resistance and improving the effectiveness of therapies in HCC.