肝脏中的TM6SF2激活抗肿瘤免疫，以抑制代谢功能障碍相关脂肪性肝病相关的肝细胞癌，并增强免疫治疗。
Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy.
作者信息
Zhang Yating, Xie Mingxu, Wen Jun, Liang Cong, Song Qian, Liu Weixin, Liu Yali, Song Yang, Lau Harry Cheuk Hay, Cheung Alvin Ho-Kwan, Man Kwan, Yu Jun, Zhang Xiang
机构信息
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guang Zhou, China.
出版信息
Gut. 2025 Mar 6;74(4):639-651. doi: 10.1136/gutjnl-2024-333154.
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 knockout ( ) 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 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of knockout was verified in orthotopic MASLD-HCC mice, while mice bearing -overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)CD8 T cells in the tumours of mice and orthotopic knockout mice, while the tumour-suppressive effect of 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 knockout in mice. Moreover, introducing 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.
背景
跨膜6超家族成员2（TM6SF2）对代谢功能障碍相关脂肪性肝病（MASLD）具有保护作用。
目的
我们旨在研究肝脏TM6SF2在MASLD相关肝细胞癌（HCC）中的机制作用和治疗潜力。
设计
用高脂肪/高胆固醇（HFHC）饮食或二乙基亚硝胺加HFHC饮食喂养肝细胞特异性敲除（ ）小鼠，以诱导MASLD-HCC。还在原位MASLD-HCC小鼠中评估了TM6SF2功能。纳入人类MASLD-HCC标本以评估临床意义。
结果
与MASLD-HCC患者的相邻正常组织相比，肿瘤中TM6SF2表达下调。肝细胞特异性敲除加剧了饮食诱导或饮食诱导加致癌物诱导的MASLD-HCC小鼠的肿瘤形成。在原位MASLD-HCC小鼠中验证了敲除的促肿瘤作用，而携带过表达肿瘤的小鼠具有相反的表型。我们观察到 小鼠和原位敲除小鼠肿瘤中干扰素-γ（IFN-γ）CD8 T细胞减少，而在耗尽CD8 T细胞后， 的肿瘤抑制作用被消除。在人类MASLD-HCC组织中证实了TM6SF2与CD8 T细胞之间的相关性，推断TM6SF2可促进抗肿瘤免疫。机制上，TM6SF2直接与IKKβ结合并抑制NF-κB信号通路以减少白细胞介素（IL）-6分泌，从而激活细胞毒性CD8 T细胞。IL-6中和消除了敲除在小鼠中的促肿瘤和免疫抑制作用。此外，通过腺病毒引入 改善了小鼠对MASLD-HCC的免疫治疗反应。
结论
肝脏TM6SF2可预防MASLD-HCC，并通过NF-κB-IL-6轴激活细胞毒性CD8 T细胞。TM且SF2是使MASLD-HCC对免疫治疗敏感的有前景的策略。
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