ArticleThe Journal of experimental medicine2025
PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion.
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Article in The Journal of experimental medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed.
- Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.Nature chemical biology · 2026Article
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Spotlight on cGAS-STING: role in disease pathogenesis and therapeutic potential.Molecular biomedicine · 2026Review
- Post-Translational Modifications: Key "Regulators" of Pancreatic Cancer Malignant Phenotype-Advances in Mechanisms and Targeted Therapies.Biomedicines · 2025Review
- Context-dependent impact of type I interferon signaling in cancer.Molecular cancer · 2025Review
- Context-dependent impact of type I interferon signaling in cancer.Molecular cancer · 2025Review
- Advances in nanomaterials for enhancing cGAS-STING pathway mediated anti-tumor treatment.Materials today. Bio · 2025Review
- A mitochondrial-related gene signature predicts prognosis and immunotherapy response in hepatocellular carcinoma.Scientific reports · 2025Article
- Transcriptome Sequencing Identifies PCK1 and IRS4 as Key Regulators of Gestational Diabetes Mellitus in Placenta: A Pilot Study.Diabetes, metabolic syndrome and obesity : targets and therapy · 2025Article
- Dual regulation of the cGAS-STING pathway: new targets and challenges for subtype-specific immunotherapy in breast cancer.Frontiers in oncology · 2025Review
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Authors and funding
31 authors.
Wenxing Qin *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.ORCID 0009-0002-7274-4917
Yuran Duan *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.ORCID 0009-0007-4597-3470
Zhiqiang Hu *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.ORCID 0000-0003-1313-3470
Yueru Hou *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.ORCID 0009-0000-3573-7473
Ting WenZhejiang 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.ORCID 0009-0005-0161-2126
Yuan OuyangLaboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.ORCID 0000-0003-4889-1271
Zheng WangZhejiang 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.ORCID 0000-0001-6277-3269
Xue SunDepartment of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.ORCID 0009-0009-2803-1048
Xiaohan ChenDepartment of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.ORCID 0000-0002-9940-4085
Katherine L WangSt. Agnes Academy , Houston, TX, USA.ORCID 0009-0009-3409-8628
Shudi LuoZhejiang 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.ORCID 0000-0002-3696-2469
Guimei JiZhejiang 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.ORCID 0009-0008-0235-2495
Yuli ShenZhejiang 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.ORCID 0000-0003-4895-7066
Bofei DongZhejiang 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.ORCID 0009-0000-6920-4288
Yanni LinZhejiang 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.ORCID 0009-0007-9440-7213
Qi TianZhejiang 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.ORCID 0009-0001-6134-8129
Zhanpeng GuoZhejiang 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.ORCID 0009-0006-2673-790X
Shiqi WuZhejiang 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.ORCID 0009-0004-4754-2226
Ling XiaoZhejiang 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.ORCID 0000-0003-4810-619X
Min LiZhejiang 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.ORCID 0009-0009-1409-1066
Liwei XiaoZhejiang 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.ORCID 0000-0001-6971-9222
Qingang WuZhejiang 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.ORCID 0000-0002-6928-6268
Ying MengZhejiang 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.ORCID 0000-0002-1165-9009
Guijun LiuZhejiang 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.ORCID 0009-0003-4491-8323
Wuchang ZhangLaboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.ORCID 0000-0002-8494-306X
Shengzhong DuanStomatology 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.ORCID 0000-0002-4866-3167
Xueli BaiZhejiang 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.ORCID 0000-0002-2934-0880
Tong LiuDepartment of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.ORCID 0000-0001-9234-1328
Jie HeDepartment 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.ORCID 0000-0002-0285-5403
Zhimin LuZhejiang 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.ORCID 0000-0002-2859-2736
Daqian XuZhejiang 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.ORCID 0000-0003-0478-2997
Funding
K.C. Wong Education FoundationMinistry of Science and Technology of the People's Republic of China 2021YFA0805600National Natural Science Foundation of China 82188102Zhejiang Natural Science Foundation LQ22H160023Zhejiang Natural Science Foundation Key Project LD22H160002Zhejiang University
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.
Indexed as
Guanosine TriphosphateMembrane ProteinsNucleotidyltransferasesPhosphoenolpyruvate Carboxykinase (GTP)Tumor EscapeAnimalsCell Line, TumorCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseFemaleHumansMicePhosphorylationSignal TransductionSTING ProteinTumor MicroenvironmentcGAS protein, humanCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseGuanosine TriphosphateMembrane ProteinsNucleotidyltransferasesPhosphoenolpyruvate Carboxykinase (GTP)STING1 protein, humanSTING Protein
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.