Liver Tumor Microenvironment Remodeling Promotes Hepatocellular Carcinoma Progression

Hepatocellular carcinoma (HCC) is a highly prevalent malignancy worldwide. Although radiofrequency ablation (RFA) is widely used for the treatment of early-stage small HCC, its 5-year recurrence rate reaches up to 70%, significantly higher than that of surgical resection, suggesting that the tumor microenvironment (TME) plays a critical role in the progression of residual tumors. Notably, in the context of non-alcoholic fatty liver disease (NAFLD), HCC patients with concurrent fatty liver have an even higher risk of post-RFA recurrence and metastasis, yet the underlying mechanisms remain unclear. Recent studies have shown that extracellular vesicles (EVs), as important mediators of intercellular communication, are abundantly released in the fatty liver microenvironment. By carrying bioactive molecules such as proteins and nucleic acids, EVs remodel the TME and promote HCC cell proliferation, migration, and immune evasion. However, how fatty liver-derived EVs specifically regulate the malignant progression of residual tumors and reshape the immune and metabolic microenvironment under conditions of local thermal stress and ischemia-hypoxia following RFA remains poorly understood. Based on these findings, this project proposes the scientific hypothesis that abnormally released EVs in the fatty liver microenvironment promote post-RFA tumor progression by remodeling the TME and inducing residual HCC cells to acquire a more aggressive phenotype. Elucidating this mechanism is of great significance for understanding the causes of high post-RFA recurrence in the context of fatty liver, identifying potential biomarkers, and developing novel adjuvant therapeutic strategies.