Activated ATF6α is a hepatic tumor driver restricting immunosurveillance

ABSTRACT:

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 demonstrate its hitherto unknown function as an ER-stress-inducing tumor-driver and metabolic master-regulator restricting cancer-immunosurveillance for HCC. ATF6α-activation in human HCC significantly correlated with an aggressive phenotype characterized by reduced patient-survival, enhanced tumor-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 gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) by binding to gene regulatory elements. 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 achieving complete response to immunotherapy displayed significantly increased ATF6α-activation compared to those with a weaker response. Targeting Atf6 via germline, 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, sensitizing to ICB. Our findings suggest persistently activated ATF6α is a tumor-driver, a potential stratification-marker for ICB response and a therapeutic target in HCC.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Nuclear Magnetic Resonance (NMR) -

PROVIDER: MTBLS13241 | MetaboLights | 2025-11-17

REPOSITORIES: MetaboLights