Lipid Metabolism and Immune Response in Hepatocellular Carcinoma: Interplay Driving Tumor Progression

With the rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), it has become a significant risk factor for hepatocellular carcinoma (HCC). This review focuses on the roles of lipid metabolism aberrations and reprogramming in HCC development. We begin with a brief overview of the relevant lipids to HCC, including fatty acyls, glycerolipids, glycerophospholipids and sterol lipids, and discuss particularly how the associated lipid metabolism and its reprogramming promotes chemoresistance in HCC. We then explore the heterogeneity in lipid distribution and metabolism across different stages of HCC development. This includes intra-tissue spatial heterogeneity across histological structure and zonated regions in the liver, and interpatient tumor heterogeneity at various degrees of resolutions, from single cell to bulk tissue levels. Next, we describe the plasticity in lipid metabolism in MASLD and HCC. With the advent of immunotherapy for HCC, we also examine the relationship between lipid metabolism and anti-tumor immunity in HCC. Finally, we address the challenges and future perspectives of targeting lipid metabolism and tumor immunity as a dual approach to improve HCC treatment.