Duan Yuran, Hu Zhiqiang, Han Peng, Lei Bo, Wang Shuo, Wang Zheng, Hou Yueru, Lin Yanni, Li Min, Xiao Liwei, Wu Qingang, Meng Ying, Liu Guijun, Lou Shenghan, Yang Laishou, Bai Xueli, Duan Shengzhong, Zhan Peng, Liu Tong, Lu Zhimin, Xu Daqian
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou, China.
Nat Cell Biol. 2025 Apr;27(4):668-682. doi: 10.1038/s41556-025-01627-8. Epub 2025 Mar 3.
Highly aggressive tumours have evolved to restrain the cGAS-STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL-STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition.
高侵袭性肿瘤已进化出抑制cGAS-STING通路以实现免疫逃逸，而这种劫持背后的机制仍不清楚。在这里，我们证明缺氧在正常乳腺上皮细胞中可诱导强烈的STING激活，但在乳腺癌细胞中则不然。从机制上讲，腺苷酸琥珀酸裂解酶（ADSL）是从头嘌呤合成中的关键代谢酶，在乳腺癌组织中高表达，并被缺氧激活的IKKβ在T350位点磷酸化。磷酸化的ADSL在内质网与STING相互作用，ADSL产生的富马酸与STING结合，导致cGAMP与STING结合受抑制、STING激活以及随后的IRF3依赖性细胞因子基因表达受抑制。破坏ADSL与STING的结合可促进STING激活并抑制肿瘤生长。值得注意的是，ADSL内质网易位阻断肽与抗PD-1抗体联合治疗对肿瘤生长具有相加抑制作用，同时免疫反应大幅增强。值得注意的是，ADSL T350磷酸化水平与STING激活水平呈负相关，并预示着乳腺癌患者的预后不良。这些发现突出了代谢物富马酸在抑制STING激活中的关键作用，并揭示了通过靶向ADSL兼职功能介导的STING抑制来改善免疫检查点治疗的新策略。
