Cholesterol’s new tricks propel MASH-HCC: impact in immunotherapy

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the end-stage of chronic liver diseases, including metabolic-associated steatohepatitis (MASH), an advanced form of metabolic dysfunction-associated steatotic liver disease. The incidence of MASH-driven HCC is expected to continue rising throughout the world due to its association with the obesity and type 2 diabetes epidemic.1 HCC has a poor prognosis with frequent recurrence and intrahepatic metastasis and effective treatment options, such as local ablative therapies, resection or transplantation are mainly limited to early disease stages.1 Unfortunately, the therapeutic armamentarium for HCC is limited, ineffective and subject to secondary or acquired chemoresistance indicating the urgent need to understand the molecular mechanisms leading to MASH-HCC that will allow the identification of new therapeutic targets for the treatment of MASH-HCC development. Although targeting programmed death-ligand 1/programmed cell death protein-1 (PD-1) in the tumour immune microenvironment (TIME) with immune checkpoint inhibitors has shown promising results in different cancer types, the impact of this approach in HCC is somewhat less effective, particularly in MASH-driven HCC tumours which harbour a unique TIME with an accumulation of an exhausted T-cell subsets (CD8+ PD-1+) contributing to the refractory response to anti-PD-1 therapy.2 Since the description that the type rather than the amount of fat drives the transition from steatosis to MASH,3 cholesterol has emerged as a crucial player in MASH pathogenesis and MASH-driven HCC development in part through the generation of bile acids (BAs) via the alternative pathway in which mitochondrial cholesterol is metabolised to the oxysterol 27-hydroxycholesterol to fuel BAs synthesis.4 Previous studies demonstrated that de novo cholesterol synthesis in the mevalonate pathway propels MASH progression5 with a crucial role of squalene epoxidase (SLQE) in MASH-HCC development whose expression is associated with poor outcome in patients with MASH-HCC. …