Targeting Tumor-Associated Macrophages and Cancer-Associated Fibroblasts to Overcome Therapeutic Resistance in Hepatocellular Carcinoma

Abstract Hepatocellular carcinoma (HCC) remains a highly lethal malignancy with limited response to current systemic therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Accumulating evidence highlights the critical role of the tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), in mediating resistance to these treatments. TAMs and CAFs drive immune evasion, extracellular matrix remodeling, angiogenesis, and the promotion of epithelial–mesenchymal transition and cancer stemness. Moreover, their crosstalk via signaling molecules such as osteopontin (SPP1) and transforming growth factor-beta (TGF-β) contributes to the formation of immunosuppressive niches and tumor immune barriers that impair therapeutic efficacy. This review summarizes the mechanisms by which TAMs and CAFs contribute to resistance to ICIs and TKIs and discusses therapeutic strategies under active investigation targeting these stromal components—including inhibition of TGF-β, IL-6, and HGF/MET pathways, TAM reprogramming via PI3Kγ or CD47 blockade, and CAF depletion using FAP-targeted approaches. Targeting the TME holds promise for overcoming therapeutic resistance and improving clinical outcomes in advanced HCC, warranting further evaluation in well-designed clinical trials.