Nicotinamide Riboside Enhances Adoptive T Cell Therapy by Promoting Memory Differentiation and Metabolic Fitness

Enhancing the efficacy of adoptively transferred T cells is essential for successful immunotherapy. The cytotoxic activity of these T cells is closely related to their mitochondrial function, which plays a critical role in T cell differentiation. This study explored the potential of nicotinamide riboside (NR), known to enhance mitochondrial function, to improve the efficacy of adoptively transferred CD8+ T cells against hepatocellular carcinoma (HCC). In subcutaneous and metastatic HCC tumor models, NR treatment significantly improved the effectiveness of adoptive T-cell therapy (ACT). NR promoted the differentiation of CD44hiCD62Lhi central memory T cells (TCM) and upregulated memory-associated genes (Tcf7, Ccr7, and Foxo1). Upon restimulation, NR-treated CD8+ T cells exhibited strong recall responses, as evidenced by metabolic reprogramming and increased cytokine production. Furthermore, RNA sequencing revealed an increased expression of Foxo1 and its target genes. Inhibition of Foxo1 partially reversed the beneficial effects of NR on mitochondrial fitness and cytotoxic function, suggesting a role for Foxo1-associated pathways in mediating these effects. In summary, NR improved mitochondrial fitness and promoted TCM differentiation, in part through a transcriptional program associated with Foxo1, thereby improving the efficacy of adoptive T-cell therapy. These findings identify NR as a promising and translatable metabolic adjuvant for HCC immunotherapy.