LAUSR

BACKGROUND & AIMS Natural killer (NK) cells are key players in tumor immunosurveillance and metabolic adaption manipulates their fate and functional state. The nicotinamide adenine dinucleotide (NAD+ ) has emerged as a vital factor to link cellular metabolism and signaling transduction. Here, we identified NAD+ metabolism as a central hub to determine the homeostasis and function of NK cells. APPROACH & RESULTS NAD+ level was elevated in activated NK cells. NAD+ supplementation not only enhanced cytokine production and cytotoxicity, but also improved the proliferation and viability of NK cells. Intriguingly, the salvage pathway was involved in maintaining NAD+ homeostasis in activated NK cells. Genetic ablation or pharmacological blockade of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway, markedly destroyed the viability and function of NK cells. Mechanistically, NAD+ salvage dictated the mitochondrial homeostasis and oxidative phosphorylation activity to support the optimal function of NK cells. However, in human hepatocellular carcinoma (HCC) tissues, NAMPT expression and NAD+ level were significantly downregulated in tumor-infiltrating NK cells (TINKs), which negatively correlated with patient survival. And, lactate accumulation in tumor microenvironment was at least partially responsible for the transcriptional repression of NAMPT in NK cells. Further, deficiency of Nampt in NK cells accelerated the growth of HCC and melanoma. Supplementation of NAD+ precursor, nicotinamide mononucleotide (NMN), significantly improved NK anti-tumor response in both mouse and human cell-derived xenograft. CONCLUSIONS These findings reveal NAD+ salvage as an essential factor for NK cell homeostasis and function, suggesting a potential strategy for invigorating NK cell-based immunotherapy.