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

Abstract

Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC). 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. TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific <i>Tm6sf2</i> knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of <i>Tm6sf2</i> knockout was verified in orthotopic MASLD-HCC mice, while mice bearing <i>Tm6sf2</i>-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)⁺CD8⁺ T cells in the tumours of <i>Tm6sf2</i> ^∆hep mice and orthotopic <i>Tm6sf2</i> knockout mice, while the tumour-suppressive effect of <i>Tm6sf2</i> 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 <i>Tm6sf2</i> knockout in mice. Moreover, introducing <i>Tm6sf2</i> by adenovirus improved immunotherapy response against MASLD-HCC in mice. 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.