Cancer-Associated Fibroblasts-Orchestrated Immune Remodeling as a Key Driver in Liver Cancer

Abstract

: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) develop within a highly immunosuppressive tumor microenvironment (TME) characterized by chronic inflammation, extensive stromal remodeling, and impaired antitumor immunity. Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as key regulators of tumor progression and immune homeostasis. This review provides an overview of CAF-mediated immune remodeling in primary liver cancers, with particular emphasis on CAF heterogeneity, CAF–immune cell interactions, and their impact on disease progression and therapeutic response. Increasing evidence indicates that CAFs orchestrate multiple aspects of the tumor immune microenvironment through the secretion of cytokines, chemokines, growth factors, and extracellular matrix components. These signals promote immune exclusion, suppress cytotoxic T-cell activity, and favor the accumulation of immunosuppressive cell populations, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Advances in single-cell and spatial transcriptomic technologies have revealed substantial CAF heterogeneity and identified distinct CAF subsets with specialized immunomodulatory functions. These findings have uncovered novel therapeutic opportunities, including CAF-targeted approaches, extracellular matrix normalization, and strategies aimed at reprogramming CAF plasticity. Overall, CAFs are central orchestrators of immune remodeling in liver cancer and contribute to the establishment of an immunosuppressive microenvironment that supports tumor progression and therapeutic resistance. Targeting CAF-driven stromal–immune interactions may enhance antitumor immunity and improve the efficacy of current and emerging immunotherapies in HCC and iCCA.