Mechanisms and therapeutic strategies of bidirectional crosstalk between hepatic stellate cell-derived cancer-associated fibroblasts and T cells in immune evasion and therapeutic resistance of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) commonly develops in the context of chronic liver injury and fibrosis, and its immune evasion and therapeutic resistance are shaped not only by tumor-intrinsic factors but also by persistent interactions between the tumor stroma and immune cells. Hepatic stellate cells (HSCs) represent an important source of cancer-associated fibroblasts (CAFs) in HCC. HSC-derived CAFs can restrict the infiltration and function of effector T cells and promote the accumulation of immunosuppressive cells through CAF-associated and multicellular signaling networks, including TGF-β/SMAD, IL-6/STAT3, CXCL12/CXCR4, and CCL2/CCR2, as well as through extracellular matrix remodeling, vascular abnormalities, hypoxia, and metabolic reprogramming. Importantly, mediators such as IL-6 and CCL2 are not specific to HSC-derived CAFs and can also be produced by immune cells, hepatocytes, and other cellular populations within the HCC microenvironment. Conversely, cytokines released by distinct T-cell subsets, including IL-17A, TGF-β, IL-10, IFN-γ, and TNF-α, can in turn shape CAF activation, inflammatory states, and matrix-remodeling programs, thereby establishing a dynamic immune-stromal feedback loop. Focusing on the heterogeneity of CAFs and T cells, this review systematically summarizes the major mechanisms underlying bidirectional crosstalk between HSC-derived CAFs and T cells and their stage-specific roles in chronic liver injury, HCC initiation, progression, and therapeutic resistance. We further discuss potential therapeutic strategies involving CAF modulation, stromal remodeling, combination immunotherapy, and patient stratification. Current evidence suggests that this crosstalk axis may provide an important framework for understanding immune exclusion and therapeutic resistance in HCC. However, its clinical translation remains constrained by CAF heterogeneity, limited targeting specificity, insufficient causal evidence in humans, and safety concerns in the setting of underlying liver disease.