Nicotinamide Riboside Enhances T Cell Function and Antitumor Immunity: Preclinical Findings

Synopsis

Most current cancer immunotherapies mainly focus on activating type 1 immune responses, which help fight cancer, but long-term remission is rare. Our study shows that a type 2 immune protein called Fc–IL-4 can directly stimulate CD8+ T cells and increase a subset called terminally exhausted CD8+ T (CD8+ TTE) cells in tumors. When combined with type 1-focused therapies, such as adoptive T cell transfer or immune checkpoint blockade, Fc–IL-4 boosts tumor-killing activity and leads to durable remission in multiple mouse and human tumor models. Mechanistically, Fc–IL-4 activates STAT6 and mTOR pathways, enhancing glycolysis and NAD+ levels in a lactate dehydrogenase A-dependent manner, which is critical for reactivating exhausted T cells. Importantly, directly giving nicotinamide riboside (NR), a NAD+ precursor, to CD8+ TTE cells can mimic these effects, increasing NAD+ levels, boosting glycolysis, and improving T cell expansion and cancer-killing ability. Overall, these findings show that Fc–IL-4, together with type 1 immunity and metabolic support like NR, offers a promising strategy to reinvigorate exhausted T cells and achieve long-lasting cancer control.

Journal

Nature