2. Academic Validation
  3. ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion

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

  • Nat Cell Biol. 2025 Mar 3. doi: 10.1038/s41556-025-01627-8.
Yuran Duan # 1 2 3,  Zhiqiang Hu # 1 2 3,  Peng Han # 4,  Bo Lei # 4,  Shuo Wang # 5,  Zheng Wang 1 2 3,  Yueru Hou 1 2 3,  Yanni Lin 1 2 3,  Min Li 1 2,  Liwei Xiao 1 2,  Qingang Wu 1 2,  Ying Meng 1 2,  Guijun Liu 1 2,  Shenghan Lou 4,  Laishou Yang 4,  Xueli Bai 1,  Shengzhong Duan 3 6,  Peng Zhan 5,  Tong Liu 4 7,  Zhimin Lu 1 2 3,  Daqian Xu 8 9 10 11
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou, China.
  • 3 Cancer Center, Zhejiang University, Hangzhou, China.
  • 4 Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
  • 6 Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
  • 7 NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China.
  • 8 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. xudaqian@zju.edu.cn.
  • 9 Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou, China. xudaqian@zju.edu.cn.
  • 10 Cancer Center, Zhejiang University, Hangzhou, China. xudaqian@zju.edu.cn.
  • 11 NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China. xudaqian@zju.edu.cn.
  • # Contributed equally.
PMID: 40033100 DOI: 10.1038/s41556-025-01627-8
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.

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