PuSH - Publication Server of Helmholtz Zentrum München

Li, X.* ; Lebeaupin, C.* ; Kadianaki, A.* ; Druelle-Cedano, C.* ; Vesper, N.* ; Rennert, C.* ; Huguet-Pradell, J.* ; Gomez Ramos, B.* ; Fan, C.* ; Piecyk, R.S.* ; Zizmare, L.* ; Ramadori, P.* ; Li, L.* ; Frick, L.* ; Qiu, M.* ; Zhang, C.* ; Martins Nascentes Melo, L.* ; Ranvir, V.P.* ; Shen, P.* ; Hanselmann, J.* ; Kosla, J.* ; Fernández-Vaquero, M.* ; Vucur, M.* ; Baskaran, P.* ; Bao, X.* ; Coleman, O.I.* ; Tang, Y.* ; Cetin, M.* ; Chen, Z.* ; Jang, I.* ; Del Prete, S.* ; Rahbari, M.* ; Zhang, P.* ; Pham, T.V.* ; Hou, Y.* ; Sun, A.* ; Gu, L.* ; Kim, L.C.* ; Rothermel, U.* ; Heide, D.* ; Ali, A.* ; Gallage, S.* ; Talvard-Balland, N.* ; Piqué-Gili, M.* ; Gris-Oliver, A.* ; Bevilacqua, A.* ; Schlicker, L.* ; Duffey, A.* ; Unger, K. ; Szydlowska, M.* ; Hetzer, J.* ; Odom, D.T.* ; Machauer, T.* ; Bucci, D.* ; Sant, P.* ; Lee, J.H.* ; Rösler, J.* ; Meckelmann, S.W.* ; Schreck, J.* ; Murray, S.* ; Simon, M.C.* ; Nahnsen, S.* ; Schulze, A.* ; Ho, P.C.* ; Jugold, M.* ; Breuhahn, K.* ; Mallm, J.P.* ; Schirmacher, P.* ; Roth, S.* ; Rahbari, N.* ; Tschaharganeh, D.F.* ; Roessler, S.* ; Goeppert, B.* ; Bengsch, B.* ; Andrieux, G.* ; Boerries, M.* ; Malek, N.P.* ; Prinz, M.* ; Weber, A.* ; Zeiser, R.* ; Tamayo, P.* ; Bronsert, P.* ; Kurowski, K.* ; Thimme, R.* ; Yuan, D.* ; Carretero, R.* ; Luedde, T.* ; Pinyol, R.* ; Hartmann, F.J.* ; Karin, M.* ; Tasdogan, A.* ; Trautwein, C.* ; Mall, M.* ; Hofmann, M.* ; Llovet, J.M.* ; Haller, D.* ; Kaufman, R.J.* ; Heikenwälder, M.*

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.

Nature 651, 796-807 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Gene-expression Signature; Hepatocellular-carcinoma; Liver-cancer; Cells; Stress; Inflammation; Metabolism; Checkpoint; Prognosis
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 651, Issue: 8106, Pages: 796-807 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Translational Metabolic Oncology (IDC-TMO)
Grants Deutsches Krebsforschungszentrum (DKFZ)