中国学者一作Nature论文：发现肝癌治疗新靶点——活化的ATF6α

Core Viewpoint - The study identifies activated ATF6α as a hepatic tumor driver that limits immune surveillance, suggesting it as a potential stratification biomarker for immune checkpoint blockade (ICB) therapy response and a new therapeutic target for hepatocellular carcinoma (HCC) [3][11]. Group 1: Research Findings - Activated ATF6α is linked to aggressive tumor phenotypes in HCC, correlating with reduced patient survival rates, accelerated tumor progression, and local immune suppression [6]. - In mouse models, liver-specific activation of ATF6α leads to progressive hepatitis, characterized by endoplasmic reticulum (ER) stress, immune suppression, and hepatocyte proliferation [6]. - The activation of ATF6α enhances glycolysis and directly inhibits gluconeogenic enzyme FBP1, with restoration of FBP1 expression limiting pathological changes associated with ATF6α activation [6][9]. Group 2: Implications for Treatment - The study suggests that long-term activation of ATF6α induces ER stress, resulting in glycolysis-dependent immune suppression in HCC, making it sensitive to ICB therapy [9]. - In HCC patients, levels of ATF6α activation are significantly higher in those with complete responses to immunotherapy compared to those with weaker responses [7]. - Targeting Atf6 through germline knockout, liver-specific knockout, or delivering therapeutic antisense oligonucleotides (ASO) can suppress HCC in preclinical mouse models [8].