Citraconate preserves T cell stemness and antitumor immunity

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.