2. Academic Validation
  3. PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion

PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion

  • J Exp Med. 2025 May 5;222(5):e20240902. doi: 10.1084/jem.20240902.
Wenxing Qin # 1 2 3 4,  Yuran Duan # 1 2,  Zhiqiang Hu # 1 2,  Yueru Hou # 1 2,  Ting Wen 1 2,  Yuan Ouyang 5 6,  Zheng Wang 1 2,  Xue Sun 7,  Xiaohan Chen 7,  Katherine L Wang 8,  Shudi Luo 1 2,  Guimei Ji 1 2,  Yuli Shen 1 2,  Bofei Dong 1 2,  Yanni Lin 1 2,  Qi Tian 1 2,  Zhanpeng Guo 1 2,  Shiqi Wu 1 2,  Ling Xiao 1 2,  Min Li 1 2,  Liwei Xiao 1 2,  Qingang Wu 1 2,  Ying Meng 1 2,  Guijun Liu 1 2,  Wuchang Zhang 5 6,  Shengzhong Duan 9,  Xueli Bai 1,  Tong Liu 7,  Jie He 10,  Zhimin Lu 1 2,  Daqian Xu 1 2 11
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University , Hangzhou, China.
  • 3 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China.
  • 4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China.
  • 5 Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology , Shanghai, China.
  • 7 Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
  • 8 St. Agnes Academy , Houston, TX, USA.
  • 9 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, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province , Hangzhou, China.
  • 10 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 11 NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China.
  • # Contributed equally.
PMID: 40048154 DOI: 10.1084/jem.20240902
Abstract

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.

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