Wenhua Li, Minmin Ge, Ziyi Luo, Minju Ni, Kexin Tang, Chenfeng Han, Jiajia Wang, Y J, Xiaowei Liu, Kaili Ma, Jingxing Yang, Wenhua Li, Cangang Zhang, Qitai Zhao, Guangcan Shao, Jaeoh Park, Yi Zhang, Yonghong Wan, Baojun Zhang, Gang Wang, Mingjing Shen, Qiang Shan, Feng Guo, Ping-Chih Ho, Liyuan Zhang, Li Zhang
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.