Activated ATF6α is a hepatic tumour driver restricting immunosurveillance

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies<sup>1</sup>. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear<sup>2</sup>. 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 stress<sup>3</sup>. 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)<sup>4</sup> 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.

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Nature
Published
2026-02-04
DOI
https://doi.org/10.1038/s41586-025-10036-8
Primary Topic
Endoplasmic Reticulum Stress and Disease
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article
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article

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance

Luiza Martins Nascentes Melo, Yingyue Tang, Jun-Hoe Lee, Niklas Vesper et al.
Nature
Endoplasmic Reticulum Stress and Disease
article

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance

Luiza Martins Nascentes Melo, Yingyue Tang, Jun-Hoe Lee, Niklas Vesper, Mirian Fernández-Vaquero, R. Zeiser, Nana Talvard-Balland, Johannes Schreck, Jonas Rösler, Zhouji Chen, Timothy V. Pham, Cangang Zhang, Randal J. Kaufman, Insook Jang, Albert Gris‐Oliver, Moritz Mall, Stéphanie Roessler, Cynthia Lebeaupin, Benjamin Goeppert, Manfred Jugold, Jan Kosla, Felix J. Hartmann, Charlotte Rennert, Kai Breuhahn, Olivia I. Coleman, Roser Pinyol, Marta Szydlowska, Robert Thimme, Alpaslan Tasdogan, Ulrike Rothermel, Kristian Unger, Susanne Roth, Suchira Gallage, Lisa Schlicker, Johannes Hanselmann, Lukas Frick, Pooja Sant, Adnan Hussein Ali, Borja Gomez Ramos, Jan‐Philipp Mallm, Jenny Hetzer, NISAR P. MALEK, Konrad Kurowski, Almut Schulze, Pierluigi Ramadori, Danijela Heide, Mihael Vucur, Yushan Hou, Stefania Prete, Miray Cetin, Praveen Baskaran, Laura C. Kim, Mohammad Rahbari, Tim Machauer, Alec Duffey, Aihua Sun, Rafael Carretero, Ping-Chih Ho, Xuanwen Bao, Clementine Druelle-Cedano, Melanie Boerries, Maike Hofmann, Peter Bronsert, Tom Luedde, Pablo Tamayo, Vikas Prakash Ranvir, Laimdota Zizmare, Peter Schirmacher, Mathias Heikenwälder, Peng Zhang, Júlia Huguet-Pradell, Sven Nahnsen, Bertram Bengsch, Peng Shen, Christoph Trautwein, Chaofan Fan, Sven W. Meckelmann, Detian Yuan, Marco Prinz, Marta Piqué-Gili, Alessio Bevilacqua, Menjie Qiu, Duncan T. Odom, Xin Li, Josep M. Llovet, Michael Karin, Sue Murray, Nuh Rahbari, M. Celeste Simon, Achim Weber, Geoffroy Andrieux, Luqing Li, Robert Stefan Piecyk, Darjus F. Tschaharganeh, Daniele Bucci, Li Gu, Aikaterini Kadianaki
article en

Abstract

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies<sup>1</sup>. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear<sup>2</sup>. 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 stress<sup>3</sup>. 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)<sup>4</sup> 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.

NatureVol. 651(8106)
University of Bern (CH), Institució Catalana de Recerca i Estudis Avançats (ES), Shandong University (CN), University of Freiburg (DE), Cancer Research Institute (US), German Cancer Research Center (DE), University of Zurich (CH), Heidelberg University (DE), Sichuan University (CN), Discovery Institute (US), Ionis Pharmaceuticals (United States) (US), University Medical Center Freiburg (DE), University Hospital Heidelberg (DE), Helmholtz Zentrum München (DE), LMU Klinikum (DE), University of California San Diego (US), Düsseldorf University Hospital (DE), West China Hospital of Sichuan University (CN), Bernstein Center for Computational Neuroscience Freiburg (DE), University Hospital of Zurich (CH), Central Institute of Mental Health (DE), Ludwig Cancer Research (CH), Essen University Hospital (DE), Research Institute for Work, Technology and Culture (DE), Heidelberg Academy of Sciences and Humanities (DE), University Children's Hospital Tübingen (DE), Klinikum Ludwigsburg (DE), Beijing Proteome Research Center (CN), DKFZ-ZMBH Alliance (DE), Deutsches Diabetes-Zentrum e.V. (DE), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), German Center for Diabetes Research (DE), Hamburg Institute for Therapy Research (DE), First Affiliated Hospital Zhejiang University (CN), Deutsches Konsortium für Translationale Krebsforschung (DE), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE), Technical University of Munich (DE), University of Pennsylvania (US), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Xi'an Jiaotong University (CN), University of Lausanne (CH), Icahn School of Medicine at Mount Sinai (US)
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