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

Menée à l'aide de modèles murins ainsi que d'échantillons tumoraux ou d'échantillons de tissus adjacents normaux prélevés sur des patients atteints d'un carcinome hépatocellulaire lié à une stéatose hépatique métabolique, cette étude met en évidence un mécanisme par lequel la protéine transmembranaire TM6SF2, en activant l'immunité antitumorale, supprime la tumeur et augmente l'efficacité des immunothérapies

Résumé en anglais

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-