Fibrosis-driven hepatocarcinogenesis, metastasis and immune evasion: Mechanisms and therapeutic targets

Hepatocellular carcinoma (HCC) arising on a background of fibrosis has fundamental mechanistic and clinical differences compared to HCC that arises in a non-fibrotic liver. The fibrotic microenvironment is characterized by extracellular matrix (ECM) remodeling, dynamic interactions with immune and stromal cells, and activation of hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs). Recent multi-omics analyses have demonstrated that these fibrotic niches dynamically promote hepatocarcinogenesis, metastasis and immune evasion. Several therapeutic strategies targeting fibrosis have improved HCC outcomes in clinical trials. These advances have facilitated an understanding of the complex mechanisms underlying fibrosis-driven HCC and are helping to optimize therapeutic prescriptions. This review synthesizes recent advances in understanding the role of fibrosis in hepatocarcinogenesis, aggressiveness, and metastasis; decodes how stromal-immune crosstalk defines immune escape through the fibrosis-driven '3C' immune evasion framework; and links mechanistic insights into fibrosis-driven HCC with emerging theranostic strategies. We emphasize that targeting fibrosis-driven oncogenic mechanisms may enhance the therapeutic efficacy in HCC, thus providing a scientific foundation for rationalizing this approach as a viable strategy against both liver fibrosis and HCC.