Denk, DominicPetrocelli, ValentinaConche, ClaireDrachsler, MoritzZiegler, Paul K.Braun, AngelaKress, AlenaNicolas, Adele M.Mohs, KathleenBecker, ChristophNeurath, Markus F.Farin, Henner F.Buchholz, Christian J.Andreux, Penelope A.Rinsch, ChrisGreten, Florian R.2023-03-132023-03-132023-03-132022-11-0810.1016/j.immuni.2022.09.014https://infoscience.epfl.ch/handle/20.500.14299/195884WOS:000924581500011T memory stem cells (T-SCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. T-SCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8(+) T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced T-SCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated beta-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to T-SCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.Immunologymitochondrialhealthimmunotherapypomegranatecolontext::journal::journal article::research article