GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326246/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326246GEOGSEfalseCitraconate preserves T cell stemness and antitumor immunityMetabolic perturbations within the tumor microenvironment profoundly compromise the stem-like properties and functionality of CD8+ T cells. Elucidating the metabolic circuitry that maintains T cell stemness is therefore essential for rejuvenating tumor-infiltrating lymphocytes and enhancing immunotherapeutic efficacy. Here, we identify citraconate, an itaconate isomer, as a critical metabolite markedly depleted in CD8+ T cells under chronic antigen stimulation or hypoxia. Citraconate supplementation preserves stem-like properties, mitigates ferroptosis, and potentiates T cell-mediated antitumor efficacy. Mechanistically, citraconate sustains intracellular cAMP pool by suppressing phosphodiesterase (PDE1A/C) expression and maintaining mitochondrial integrity, thereby activating protein kinase A (PKA) signaling. This activation represses arachidonate-5-lipoxygenase (ALOX5) transcription, reducing arachidonic acid peroxidation. Clinically, reduced ALOX5 or PDE1A expression correlates with decreased T cell exhaustion and enhanced responses to immune checkpoint blockade (ICB) therapy. Our findings reveal the citraconate-mediated PDE1-cAMP-ALOX5 axis as a promising therapeutic target for potentiating cancer immunotherapy.2026/04/06GSE326246GSM9626133GSM9642095GSM9626132GSM9626131GSM9626130GSM9626126GSM9626129GSM9626128GSM962612719057326246Mus musculus