biostudies-literatureZhang YHealth and Medical Research Fund Hong KongRGC Theme-based Research SchemeNational Natural Science Foundation of ChinaResearch Grants Council of the Hong Kong Special Administrative RegionCUHK Research Startup Fund639-651https://www.ebi.ac.uk/biostudies/studies/S-EPMC12014897biostudies-literatureUnknown74(4)<h4>Background</h4>Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).<h4>Objective</h4>We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC).<h4>Design</h4>Hepatocyte-specific <i>Tm6sf2</i> knockout (<i>Tm6sf2</i> ^∆hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance.<h4>Results</h4>TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific <i>Tm6sfGutHepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy.PMC12014897FPU/2023/149822726198222290108191336CUHK 1411742282103355T12-703/19-RCUHK 1411712307210097CUHK 14119524Cheung AHXie MYu JLau HCHLiu WMan KLiang CLiu YWen JZhang YSong QZhang XSong YfalseHepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy.<h4>Background</h4>Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).<h4>Objective</h4>We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC).<h4>Design</h4>Hepatocyte-specific <i>Tm6sf2</i> knockout (<i>Tm6sf2</i> ^∆hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance.<h4>Results</h4>TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific <i>Tm6sf2025-01-01T00:00:00Z2025 Mar2026-07-15T11:05:46.482Z2025-07-03T03:04:39.275ZS-EPMC120148973966790610.1136/gutjnl-2024-333154