The tumor microenvironment (TME) is profoundly immunosuppressive, not least due to its tendency to induce a state of dysfunction known as exhaustion in cytotoxic (CD8+) T cells (CTLs). Researchers led by Ludwig Lausanne’s Ping-Chih Ho and colleagues in China reported in a May paper that made the cover of Science Immunology that citraconate—an isomer of the anti-inflammatory metabolite produced by macrophages, itaconate—maintains the stemness of CTLs, attenuating their exhaustion and augmenting their anti-tumor activity. The isomer, they show, is depleted in CTLs from mouse models and patient samples that have been subjected to the hypoxia and chronic antigen stimulation in the TME that induces exhaustion. Treating exhausted T cells from human tumors with citraconate in cell culture restored their activation and stemness while reducing their expression of markers associated with exhaustion. Probing deeper, the researchers found that citraconate inhibits phosphodiesterase1A/C (PDE1A/C) expression and maintains adequate levels of cAMP, supporting mitochondrial integrity. This, in turn, leads to protein kinase A signaling and repression of arachidonate-5-lipoxygenase (ALOX5) transcription, which suppresses arachidonic acid peroxidation and prevents a type of cell death known as ferroptosis. Patient samples revealed that low ALOX5 or PDE1A expression correlate with less CTL exhaustion and improved responses to immune checkpoint blockade therapy, supporting the clinical relevance of the citraconate-PDE1-cAMP-ALOX5 axis as a target for the enhancement of cancer immunotherapy.
Citraconate preserves T cell stemness and antitumor immunity
Science Immunology, 2026 May 1