Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications.

Hepatocellular carcinoma (HCC) remains difficult to treat because responses to tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are limited and heterogeneous. Cancer-associated fibroblasts (CAFs) can influence therapeutic responses through paracrine signaling, immune regulation, and extracellular matrix remodeling, but CAF-driven tumor progression should not be equated with therapeutic resistance. This review critically evaluates HCC-specific evidence according to defined drug exposure, treatment-related outcomes, and functional rescue. The most mechanistically resolved direct resistance mechanisms involve CAF-derived SPP1, which activates integrin-PKCα-dependent bypass signaling during sorafenib or lenvatinib treatment; CAF-derived CXCL12, which reduces sorafenib-induced apoptosis through CXCR4-dependent FOLR1 upregulation; and CAF-derived fibronectin extra domain A, which activates NF-κB-SHMT1-dependent redox adaptation during sorafenib exposure, with TLR4 proposed as the upstream receptor. These pathways are supported by genetic or pharmacological interventions that restore TKI sensitivity. By contrast, POSTN⁺ CAFs are associated with IL-6/IL-6R/STAT3-dependent macrophage recruitment, increased macrophage SPP1 expression, immune exclusion, and reduced ICI responsiveness, although selective reversal of this CAF program remains unproven. Progression-associated and cross-cancer findings are therefore considered separately from established resistance mechanisms.