Disrupting the NAD+/NAM metabolic ratio driven by IL-1β inflammatory response potentiates chemotherapy and chemoimmunotherapy in mice

Nicotinamide adenine dinucleotide (NAD+) replenishment sensitizes tumors to immunotherapy. However, chemotherapy-induced NAD+ metabolic reprogramming remains poorly understood. Here, we show that chemotherapy induces a macrophage-dependent IL-1β inflammatory response and NAD+ metabolic reprogramming, thereby conferring chemoresistance via CD44. Mechanistically, IL-1β-induced NAD+ salvage cooperates with the clearance of nicotinamide (NAM), the physiological inhibitor of the NAD+-consuming enzymes sirtuins, to drive CD44-mediated chemoresistance by boosting the NAD+/NAM ratio for sirtuin activation. NAM phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage recycles NAD+ from NAM and further triggers serine biosynthesis, ultimately supporting NAM N-methyltransferase (NNMT)-mediated NAM clearance. Importantly, NAMPT inhibition disrupts the NAD+/NAM ratio and mitigates CD44-mediated chemoresistance and NK cell dysfunction, ultimately enhancing the efficacy of chemoimmunotherapy when combined with IL-2 across multiple preclinical models of solid tumors. Thus, our findings underscore the NAD+/NAM ratio as a metabolic therapeutic target for enhancing chemotherapy and NK cell-based chemoimmunotherapy efficacy. NAD+ metabolic pathways regulate tumor growth and sensitivity to therapeutic treatment. However, the effects of chemotherapy and chemoimmunotherapy regimens on NAD metabolism remain unclear. Here, the authors identify a macrophage-driven IL-1β inflammatory signaling that regulates the NAD + /NAM metabolic ratio to drive CD44-mediated chemoresistance and NK cell dysfunction and show that disruption of the NAD + /NAM ratio sensitises tumors to chemoimmunotherapy across multiple preclinical mouse models.