Lipid metabolism remodeling the immunological landscape of hepatocellular carcinoma: From mechanisms to therapeutics.

Hepatocellular carcinoma (HCC) remains a major global malignancy with high incidence and poor survival rates. Etiology-driven metabolic-immune interactions have emerged as a unifying framework for deciphering hepatocarcinogenesis. Hepatitis B virus (HBV) and metabolic dysfunction-associated steatotic liver disease (MASLD) are the two predominant etiological drivers for HCC. Although immunotherapy serves as a cornerstone of HCC treatment, therapeutic response varies considerably across distinct etiologies. Accumulating evidence suggests that etiology-specific dysregulation of lipid metabolism shapes immune imbalance in the tumor microenvironment, thereby accounting for the heterogeneous responses to immunotherapy. Therefore, deciphering etiology-driven metabolic-immune crosstalk may provide new opportunities to improve therapeutic responses. In this review, we propose the framework of etiology-driven metabolic-immune interactions by comparing two major etiologies, HBV and MASLD. Moreover, taking into account the crucial role of lipid metabolism in hepatocarcinogenesis, dietary interventions and lipid metabolism-targeted therapies have also been included so as to offer potential therapeutic strategies.