浙江大学许大千团队开发出ADSL生成的富马酸盐结合并抑制STING促进肿瘤免疫逃逸。这一研究成果于2025年3月3日发表在国际顶尖学术期刊《自然—细胞生物学》上。

在这里，课题组人员证明了缺氧诱导正常乳腺上皮细胞的强大STING激活，但在乳腺癌细胞中没有。腺苷琥珀酸裂解酶（ADSL）是新生嘌呤合成的关键代谢酶，在乳腺癌组织中高表达，并在T350位点被缺氧激活的IKKβ磷酸化。磷酸化的ADSL在内质网与STING相互作用，ADSL产生的富马酸盐与STING结合，导致cGAMP与STING结合、STING激活以及随后的IRF3依赖性细胞因子基因表达受到抑制。破坏ADSL-STING结合可促进STING的激活并抑制其生长。

值得注意的是，ADSL内质网易位阻断肽和抗PD-1抗体联合治疗可诱导肿瘤生长的累加性抑制作用，并显著增强免疫应答。值得注意的是，ADSL T350磷酸化水平与STING激活水平呈负相关，并预示乳腺癌患者预后不良。这些发现强调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-月光功能介导的STING抑制来改善免疫检查点治疗的新策略。

研究人员表示，高侵袭性肿瘤已经进化到抑制cGAS-STING免疫逃避途径，这种劫持的机制尚不清楚。

附：英文原文

Title: ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion

Author: 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

Issue&Volume: 2025-03-03

Abstract: 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.

DOI: 10.1038/s41556-025-01627-8

Source: https://www.nature.com/articles/s41556-025-01627-8