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Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR\u00a0transducer ATF6\u03b1 remains unclear\n                    <jats:sup>2<\/jats:sup>\n                    . Here\u00a0we demonstrate the\u00a0function of\u00a0ATF6\u03b1 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 stress\n                    <jats:sup>3<\/jats:sup>\n                    . ATF6\u03b1 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 ATF6\u03b1 activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6\u03b1 increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6\u03b1-activation-related pathologies. Prolonged ATF6\u03b1 activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)\n                    <jats:sup>4<\/jats:sup>\n                    restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6\u03b1 activation compared with those with a weaker response. Targeting\n                    <jats:italic>Atf6<\/jats:italic>\n                    through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6\u03b1 activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6\u03b1 is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-10036-8","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T16:02:54Z","timestamp":1770220974000},"page":"796-807","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Activated ATF6\u03b1 is a hepatic tumour driver restricting 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