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.
肝细胞癌（HCC）是癌症相关死亡率增长最快的病因，且现有疗法有限¹。尽管内质网（ER）应激和未折叠蛋白反应（UPR）与HCC相关，但UPR转导因子ATF6α的具体作用仍不明确²。本研究发现ATF6α作为内质网应激诱导的肿瘤驱动因子和代谢核心调控因子，通过限制癌症免疫监视促进HCC进展——这与其经典的内质网应激适应性反应功能形成鲜明对比³。人类HCC中ATF6α的激活与侵袭性肿瘤表型显著相关，表现为患者生存期缩短、肿瘤进展加速及局部免疫抑制。小鼠肝细胞特异性ATF6α激活可诱发进行性肝炎，伴随内质网应激、免疫抑制和肝细胞增殖。同时，激活的ATF6α通过结合基因调控元件增强糖酵解并直接抑制糖异生酶FBP1的表达。恢复FBP1表达可缓解ATF6α激活相关的病理改变。肝细胞中持续激活的ATF6α会触发肝癌发生、瘤内T细胞浸润及营养匮乏性免疫耗竭。免疫检查点阻断（ICB）⁴可恢复免疫监视并减少HCC发生。一致地，对免疫治疗完全应答的HCC患者较应答较差者呈现显著增强的ATF6α激活。通过种系敲除、肝细胞特异性敲除或治疗性递送反义寡核苷酸靶向Atf6，可在临床前肝癌模型中抑制HCC进展。因此，持续激活的ATF6α驱动内质网应激，通过糖酵解依赖性机制诱导肝癌免疫抑制，并增强对ICB的敏感性。本研究表明，持续性激活的ATF6α是肿瘤驱动因子、ICB应答的潜在分层标志物及HCC治疗靶点。
Activated ATF6α is a hepatic tumour driver restricting immunosurveillance
肿瘤(癌症)患者之家