Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy.

BACKGROUND: Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD). OBJECTIVE: We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC). DESIGN: Hepatocyte-specific Tm6sf2 knockout (Tm6sf2 (∆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. RESULTS: TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific Tm6sf2 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of Tm6sf2 knockout was verified in orthotopic MASLD-HCC mice, while mice bearing Tm6sf2-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)(+)CD8(+) T cells in the tumours of Tm6sf2 (∆hep) mice and orthotopic Tm6sf2 knockout mice, while the tumour-suppressive effect of Tm6sf2 was abolished after depleting CD8(+) T cells. The correlation between TM6SF2 and CD8(+) T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8(+) T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of Tm6sf2 knockout in mice. Moreover, introducing Tm6sf2 by adenovirus improved immunotherapy response against MASLD-HCC in mice. CONCLUSION: Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8(+) T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.