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

作者：Yating Zhang, Mingxu Xie, Jun Wen, Cong Liang, Qian Song, Weixin Liu, Yali Liu, Yang Song, Harry Cheuk-Hay Lau, Alvin H.K. Cheung, Kwan Man, Jun Yu, Xiang Zhang · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2024-333154 · 被引用次数：20 · 研究领域：Liver Disease Diagnosis and Treatment、Liver physiology and pathology、Liver Diseases and Immunity

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 redu...