biostudies-literatureTang WResearch Grants Council, University Grants CommitteeTerry Fox FoundationLi Ka Shing FoundationAstraZeneca834-847https://www.ebi.ac.uk/biostudies/studies/S-EPMC9243114biostudies-literatureUnknown19(7)Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to pCellular & molecular immunologyAberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.PMC92431141410541914104820Terry Fox FoundationLi Ka Shing FoundationC4045-18WAstraZeneca Research Program (2017)Lai PBSLiang ZMok MTSNg KKCWong VWSZhang LWong SKHWang JHou YWu HLiu XXiong ZTo KFYeung PCLee HMKong APSCheng ASLTang WSun HWong JSung JJYZhou JLi JFeng YZeng XLam CCHYang WTian XLu JLeung HHWChan AWHfalseAberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to p2022-01-01T00:00:00Z2022 Jul2026-05-28T01:31:53.198Z2025-02-19T01:18:13.107ZS-EPMC92431143559581910.1038/s41423-022-00872-3