近日，德国慢性炎症与癌症科教授Mathias Heikenwälder及其课题组研究出活化的ATF6α是限制免疫监测的肝脏肿瘤驱动因子。相关论文于2026年2月4日发表在《自然》杂志上。

在这里，研究人员证明了ATF6α作为内质网应激诱导的肿瘤驱动因子和限制HCC癌症免疫监视的代谢主调节剂的功能，而不是其作为内质网应激的适应性反应的良好特征。ATF6α在人类HCC中的激活与侵袭性肿瘤表型显著相关，其特征是患者生存率降低、肿瘤进展加快和局部免疫抑制。肝细胞特异性ATF6α激活小鼠可诱导进行性肝炎伴内质网应激、免疫抑制和肝细胞增殖。同时，激活的ATF6α增加糖酵解，并通过与基因调控元件结合直接抑制糖异生酶FBP1。恢复FBP1的表达限制了ATF6α激活相关的病理。肝细胞中ATF6α激活的延长引发肝癌发生、瘤内T细胞浸润和营养剥夺性免疫衰竭。免疫检查点阻断（ICB）恢复免疫监视并减少HCC。

一致地，与免疫治疗反应较弱的HCC患者相比，对免疫治疗达到完全反应的HCC患者显示出显著增加的ATF6α激活。通过种系消融术、肝细胞特异性消融术或治疗性肝细胞递送反义寡核苷酸靶向Atf6可抑制临床前肝癌模型中的HCC。因此，延长的ATF6α激活驱动内质网应激，导致肝癌中糖酵解依赖性免疫抑制和对ICB的敏感性。他们的研究结果表明，持续激活的ATF6α是肿瘤驱动因子，是ICB反应的潜在分层标记物，也是HCC的治疗靶点。

研究人员表示，肝细胞癌（HCC）是癌症相关死亡率增长最快的疾病，治疗方法有限。虽然内质网（ER）应激和未折叠蛋白反应（UPR）与HCC有关，但UPR传感器ATF6α的参与尚不清楚。

附：英文原文

Title: Activated ATF6α is a hepatic tumour driver restricting immunosurveillance

Author: Li, Xin, Lebeaupin, Cynthia, Kadianaki, Aikaterini, Druelle-Cedano, Clementine, Vesper, Niklas, Rennert, Charlotte, Huguet-Pradell, Jlia, Gomez Ramos, Borja, Fan, Chaofan, Piecyk, Robert Stefan, Zizmare, Laimdota, Ramadori, Pierluigi, Li, Luqing, Frick, Lukas, Qiu, Menjie, Zhang, Cangang, Martins Nascentes Melo, Luiza, Ranvir, Vikas Prakash, Shen, Peng, Hanselmann, Johannes, Kosla, Jan, Fernndez-Vaquero, Mirian, Vucur, Mihael, Baskaran, Praveen, Bao, Xuanwen, Coleman, Olivia I., Tang, Yingyue, Cetin, Miray, Chen, Zhouji, Jang, Insook, Del Prete, Stefania, Rahbari, Mohammad, Zhang, Peng, Pham, Timothy V., Hou, Yushan, Sun, Aihua, Gu, Li, Kim, Laura C., Rothermel, Ulrike, Heide, Danijela, Ali, Adnan, Gallage, Suchira, Talvard-Balland, Nana, Piqu-Gili, Marta, Gris-Oliver, Albert, Bevilacqua, Alessio, Schlicker, Lisa, Duffey, Alec, Unger, Kristian, Szydlowska, Marta, Hetzer, Jenny, Odom, Duncan T., Machauer, Tim, Bucci, Daniele, Sant, Pooja, Lee, Jun-Hoe, Rsler, Jonas, Meckelmann, Sven W., Schreck, Johannes, Murray, Sue, Simon, M. Celeste, Nahnsen, Sven

Issue&Volume: 2026-02-04

Abstract: Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear2. Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.

DOI: 10.1038/s41586-025-10036-8

Source: https://www.nature.com/articles/s41586-025-10036-8