Citraconate preserves T cell stemness and antitumor immunity
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.
Authors
- Qitai Zhao (ORCID: https://orcid.org/0000-0003-4023-2060)
- Cangang Zhang (ORCID: https://orcid.org/0000-0001-6443-7023)
- Chenfeng Han
- Qiang Shan (ORCID: https://orcid.org/0000-0002-7717-2922)
- Y J
- Jaeoh Park (ORCID: https://orcid.org/0000-0003-2699-371X)
- Yonghong Wan (ORCID: https://orcid.org/0000-0001-7034-1722)
- Minmin Ge
- Kexin Tang (ORCID: https://orcid.org/0000-0001-9147-7995)
- Wenhua Li (ORCID: https://orcid.org/0000-0002-9457-6662)
- Xiaowei Liu (ORCID: https://orcid.org/0000-0001-7951-0879)
- Li Zhang (ORCID: https://orcid.org/0000-0001-8142-403X)
- Ziyi Luo (ORCID: https://orcid.org/0009-0009-8363-5581)
- Mingjing Shen (ORCID: https://orcid.org/0000-0002-7918-0803)
- Kaili Ma
- Jingxing Yang
- Feng Guo
- Baojun Zhang
- Guangcan Shao
- Gang Wang
- Minju Ni
- Liyuan Zhang
- Ping-Chih Ho
- Yi Zhang
- Jiajia Wang
Institutions
- Xuzhou Medical College (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Soochow University (CN)
- Suzhou Municipal Hospital (CN)
- Ludwig Cancer Research (CH)
- Suzhou Institute of Systems Medicine (CN)
- Second Affiliated Hospital of Soochow University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Xi'an Jiaotong University (CN)
- University of Lausanne (CH)
- McMaster University (CA)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-05-01
- DOI
- https://doi.org/10.1126/sciimmunol.adz0348
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province
- National Key Research and Development Program of China