Citraconate preserves T cell stemness and antitumor immunity

  • Sci Immunol. 2026 May;11(119):eadz0348. doi: 10.1126/sciimmunol.adz0348.
Wenhui Li  1  2 ,  Minmin Ge  1  2 ,  Ziyi Luo  1  2 ,  Minju Ni  1  2 ,  Kexin Tang  1  2 ,  Chenfeng Han  1  2 ,  Jiajia Wang  1  2 ,  Yifu Ma  3  4 ,  Xiaowei Liu  1  2 ,  Kaili Ma  1  2 ,  Jingxing Yang  1  2 ,  Wenjing Li  1  2  5 ,  Cangang Zhang  6  7  8  9 ,  Qitai Zhao  10 ,  Guangcan Shao  11 ,  Jaeoh Park  12  13 ,  Yi Zhang  10 ,  Yonghong Wan  14 ,  Baojun Zhang  6  7  8  9 ,  Gang Wang  15 ,  Mingjing Shen  16 ,  Qiang Shan  1 ,  Feng Guo  5 ,  Ping-Chih Ho  12  13 ,  Liyuan Zhang  3  4 ,  Lianjun Zhang  1  2
Affiliations
  • 1. National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou 215123, Jiangsu, China.
  • 2. Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou 215123, Jiangsu, China.
  • 3. Center for Cancer Diagnosis and Treatment, Second Affiliated Hospital of Soochow University, Suzhou 215123, Jiangsu, China.
  • 4. PRAG Therapy Center, Second Affiliated Hospital of Soochow University, Suzhou 215123, Jiangsu, China.
  • 5. Department of Oncology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, China.
  • 6. Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 7. Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
  • 8. Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 9. Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shaanxi, China.
  • 10. Biotherapy Center and Cancer Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 11. Multi-Omics Mass Spectrometry Facility, Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China.
  • 12. Department of Oncology, University of Lausanne, Lausanne, Switzerland.
  • 13. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
  • 14. McMaster Immunology Research Center, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
  • 15. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China.
  • 16. Department of Thoracic Surgery, Second Affiliated Hospital of Soochow University, Suzhou, China.
PMID: 42066062 DOI: 10.1126/sciimmunol.adz0348
Abstract

Metabolic perturbations in the tumor microenvironment profoundly compromise the stemlike properties and effector functions of CD8 T cells. Deciphering the metabolic circuitry that sustains T cell stemness is critical for reinvigorating tumor-infiltrating lymphocytes and augmenting immunotherapeutic efficacy. Here, we identify citraconate, an itaconate isomer, as a metabolite markedly depleted in CD8 T cells subjected to chronic antigen stimulation or hypoxic conditions. Citraconate supplementation preserves stemlike characteristics, attenuates Ferroptosis, and potentiates T cell-mediated antitumor immunity. Mechanistically, citraconate maintains intracellular cyclic adenosine monophosphate (cAMP) concentrations by suppressing phosphodiesterase1A/C (PDE1A/C) expression and preserving mitochondrial integrity, thereby activating protein kinase A (PKA) signaling. This activation transcriptionally represses arachidonate-5-lipoxygenase (ALOX5), consequently reducing arachidonic acid peroxidation. Clinically, diminished ALOX5 or PDE1A expression correlates with reduced T cell exhaustion and improved responses to immune checkpoint blockade (ICB) therapy. Our findings reveal the citraconate-mediated PDE1-cAMP-ALOX5 axis as a potential therapeutic target for enhancing Cancer Immunotherapy.

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