PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion
Hypoxia induces immunosuppressive phenotypes in tumor cells even in the presence of cytosolic DNA accumulation. The mechanisms by which tumor cells suppress hypoxia-induced cGAS-STING activation for immune evasion remain largely unclear. Here, we demonstrate that hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis. This phosphorylation triggers the interaction between PCK1 and cGAS. The PCK1 associated with cGAS competitively consumes GTP, a substrate shared by both PCK1 and cGAS. Consequently, PCK1 inhibits GTP-dependent cGAS activation and subsequent STING-promoted immune cell infiltration and activation in the tumor microenvironment, leading to promoted tumor growth in mice. The blockade of PCK1 function, in combination with anti-PD-1 antibody treatment, exhibits an additive therapeutic effect on tumor growth. Additionally, PCK1 S151 phosphorylation is inversely correlated with cGAS-STING activation in human breast cancer specimens and patient survival. These findings reveal a novel regulation of cGAS-STING pathway and uncover the metabolic control of immune response in tumor cells.
Authors
- Zhimin Lu (ORCID: https://orcid.org/0000-0002-2859-2736)
- Yu‐Li Shen (ORCID: https://orcid.org/0000-0003-4895-7066)
- Ouyang Yuan (ORCID: https://orcid.org/0000-0003-4889-1271)
- Qingang Wu (ORCID: https://orcid.org/0000-0002-6928-6268)
- X. Chen (ORCID: https://orcid.org/0000-0002-9940-4085)
- Bofei Dong
- Wuchang Zhang (ORCID: https://orcid.org/0000-0002-8494-306X)
- Shudi Luo (ORCID: https://orcid.org/0000-0002-3696-2469)
- Xueli Bai (ORCID: https://orcid.org/0000-0002-2934-0880)
- Guimei Ji
- G.Z. Liu
- Zheng Wang (ORCID: https://orcid.org/0000-0001-6277-3269)
- Liwei Xiao (ORCID: https://orcid.org/0000-0001-6971-9222)
- Ying Meng (ORCID: https://orcid.org/0000-0002-1165-9009)
- Xue Sun
- Z. Hu (ORCID: https://orcid.org/0000-0003-1313-3470)
- Daqian Xu (ORCID: https://orcid.org/0000-0003-0478-2997)
- K Wang
- Yuran Duan (ORCID: https://orcid.org/0009-0007-4597-3470)
- Tong Liu (ORCID: https://orcid.org/0000-0001-9234-1328)
- Qi Tian (ORCID: https://orcid.org/0000-0001-8389-5484)
- Jie He (ORCID: https://orcid.org/0000-0002-0285-5403)
- Yanhong Hou (ORCID: https://orcid.org/0000-0003-2248-8441)
- Yanni Lin
- Ling Xiao (ORCID: https://orcid.org/0000-0003-4810-619X)
- Zhanpeng Guo
- Ting Wen
- Wenxing Qin
- Shengzhong Duan (ORCID: https://orcid.org/0000-0002-4866-3167)
- Shiqi Wu
- Min Li (ORCID: https://orcid.org/0000-0001-8786-5629)
Institutions
- Shanghai Medical College of Fudan University (CN)
- Harbin Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Ninth People's Hospital (CN)
- Third Affiliated Hospital of Harbin Medical University (CN)
- St. Albans School (US)
- National Clinical Research (US)
- Stomatology Hospital (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1084/jem.20240902
- Citations
- 6
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 4.78
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Zhejiang University
- Tianjin Medical University
- K. C. Wong Education Foundation
- Natural Science Foundation of Zhejiang Province