PXD045903

PXD045903 is an original dataset announced via ProteomeXchange.

Title	Chronic ATF6-driven ER-stress increases glucose-consumption causing nutrient-deprived immunosuppression and liver cancer
Description	Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. In contrast to the well-characterized role of ATF6α-activation as an adaptive response to ER-stress, we here demonstrate its hitherto unknown function as an ER stress-inducing oncoprotein and metabolic master-regulator restricting cancer-immunosurveillance. In human HCC, ATF6α-activation significantly correlated with reduced patient-survival, tumor-progression, local immunosuppression, and higher recurrence rates of liver-cancer upon hepatectomy. Hepatocyte-specific ATF6α-activation in mice induced progressive hepatitis with ER-stress, immunosuppression, and hepatocyte-proliferation. Concomitantly, activated-ATF6α increased glycolysis and repressed gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1). Restoring FBP1 expression prevented ATF6α-activation-related pathologies. Prolonged ATF6α-activation in hepatocytes triggered hepatocarcinogenesis, intratumoral T-cell infiltration, and nutrient-deprived immune-exhaustion. Immune-checkpoint blockade (ICB) efficiently restored immunosurveillance and dramatically reduced HCC. In line, HCC patients with a significantly higher ATF6α-activation signature presented complete response to ICB monotherapy. Targeting Atf6 via germline, hepatocyte-specific ablation, or therapeutic delivery of antisense-oligonucleotides dampened HCC in preclinical liver-cancer models. Thus, prolonged ATF6α-activation drives ER-stress, leading to aberrant glucose metabolism-dependent immunosuppression in liver cancer. Our findings propose persistently activated ATF6α as an oncoprotein, stratification-marker for liver-cancer ICB, and targetable therapeutic strategy against HCC.
HostingRepository	PRIDE
AnnounceDate	2026-01-27
AnnouncementXML	Submission_2026-01-27_07:58:09.305.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sven Nahnsen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-04 12:15:57	ID requested
⏵ 1	2026-01-27 07:58:09	announced

10.1038/S41586-025-10036-8;

submitter keyword: ATF6, HCC,ER stress, glucose, Liver, Immune-checkpoint blockade

Mathias Heikenwälder
contact affiliation	German Cancer Research Center (DKFZ) Foundation under Public Law Im Neuenheimer Feld 280 69120 Heidelberg Germany
contact email	m.heikenwaelder@dkfz-heidelberg.de
lab head
Sven Nahnsen
contact affiliation	Biomedical Data Science, Department of Computer Science, University of Tübingen
contact email	sven.nahnsen@uni-tuebingen.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/01/PXD045903

PRIDE project URI

• PRIDE
  1. PXD045903
     1. Label: PRIDE project
     2. Name: Chronic ATF6-driven ER-stress increases glucose-consumption causing nutrient-deprived immunosuppression and liver cancer