Urolithin-A promotes CD8+ T cell-mediated cancer immunosurveillance via FOXO1 activation.

Naïve T cells are key players in cancer immunosurveillance, even though their function declines during tumor progression. Thus, interventions capable of sustaining the quality and function of naïve T cells are needed to improve cancer immunoprevention. In this context, we studied the capacity of Urolithin-A (UroA), a potent mitophagy inducer, to enhance T-cell mediated cancer immunosurveillance. We discovered that UroA improved the cancer immune response by activating the transcription factor FOXO1 in CD8+ T cell. Sustained FOXO1 activation promoted the expression of the adhesion molecule L-selectin (CD62L) resulting in the expansion of the Naïve T cells population. We found that UroA reduces FOXO1 phosphorylation favoring its nuclear localization and transcriptional activity. Overall, our findings determine FOXO1 as a novel molecular target of UroA in CD8+T cells and indicate UroA as promising immunomodulator to improve cancer immunosurveillance.