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.

Significance: Urolithin-A, a potent Mitophagy inducer, emerges as a promising tool to enhance Cancer immunosurveillance by activating the FOXO1 transcription factor in CD8+ T cells. This activation promotes the expansion of naïve T cells, offering a novel avenue for improving Cancer immune response and highlighting UroA as a potential immunomodulator for bolstering our body's defenses against Cancer.