Effect of Nicotinamide Riboside Against the Exhaustion of CD8+ T Cells via Alleviating Mitochondrial Dysfunction

Background: Targeting mitochondria and protecting the mitochondrial function of CD8+ T cells are crucial for enhancing the clinical efficacy of cancer immunotherapy. Objectives: In this study, our objective was to investigate the potential of nicotinamide riboside (NR) in preserving the mitochondrial function of CD8+ T cells and mitigating their exhaustion. Methods: We established two in vitro models to induce CD8+ T cell exhaustion either by tumor cell-conditioned medium (TCM) or by continuous stimulation with OVA(257–264) peptide. CD8+ T cells were treated in the absence/presence of NR. Results: Our findings demonstrated that NR supplementation effectively inhibited CD8+ T cell exhaustion and preserved mitochondrial function in both models. Moreover, apoptosis of CD8+ T cells was reduced after NR treatment. Western blot data indicated that NR treatment upregulated Silent information regulator 1 (SirT1) expression. Further inhibition of Sirt1 activity using EX527 uncovered that the inhibitory effect of NR on CD8+ T cell exhaustion and its protective effect on mitochondria were attenuated. Conclusions: In conclusion, our results indicate that NR supplementation attenuates CD8+ T cell exhaustion, and its underlying mechanism is associated with increased mitochondrial function regulated by the SirT1 pathway. Our research provides evidence that NR may assist in enhancing the clinical efficacy of immunotherapy.