NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.

Chronic antigen exposure drives CD8+ T cell exhaustion; however, strategies to maintain a long-lived, functional CD8+ T cell population under chronic stimulation remain unclear. In this study, we demonstrate that overexpression of nitric oxide synthase-interacting protein (NOSIP) enhances the persistence of antigen-specific CD8+ T cells under chronic antigen stimulation. Notably, NOSIP overexpression preserved a less differentiated CX3CR1neg subset and inhibited its progression toward an apoptosis-prone CX3CR1hi state, which was associated with reducing cell death and promoting long-term persistence. In a tumor model, NOSIP-overexpressing CD8+ T cells exhibited improved tumor control, indicating that NOSIP-mediated persistence confers superior antitumor capacity. Furthermore, NOSIP overexpression increased the responsiveness of CD8+ T cells to programmed death-ligand 1 blockade, suggesting that NOSIP may represent a promising therapeutic target.