Hepatocarcinogenesis and metabolic control of immunosuppression by ATF6a-driven ER-stress

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapy. While endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the role of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. In sharp contrast to the well-characterized role of ATF6α as an adaptive response to ER-stress, we here demonstrate that chronic ATF6α-activation is a hitherto unknown immune-metabolic master regulator in driving liver cancer: We establish ATF6α-activation in human chronic-hepatitis and HCC, unexpectedly associated with tumor-progression and correlated with reduced patient-survival. Chronic, hepatocyte-specific activation of ATF6α in mice induced early onset liver injury with ER-stress, DNA-damage, and hepatocyte-proliferation. Aged mice with hepatocyte-specific ATF6α-activation developed spontaneous liver-cancer due to oncogenic signaling in hepatocytes and an immunosuppressive microenvironment. Targeting Atf6 via germline, hepatocyte-specifically or by therapeutic hepatocyte-delivery of antisense-oligonucleotides dampened HCC in distinct preclinical liver-cancer models. Here, we identify chronic ATF6a-activation to drive ER-stress, bridging aberrant liver metabolism with immunosuppression in hepatocarcinogenesis.

Publication History

Article published online:
20 January 2025