A context-dependent framework for targeting NAD metabolism in cancer

Nicotinamide adenine dinucleotide (NAD) occupies a privileged position at the intersection of cellular bioenergetics, redox homeostasis, and signal transduction. Beyond its canonical role in ATP synthesis, NAD serves as an obligate cofactor for enzymes including poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, thereby regulating DNA repair, epigenetic remodeling, and inflammatory signaling. Thus, NAD metabolism supports the preservation of cellular homeostasis against oncogenic insults. Malignant transformation, however, imposes substantial biosynthetic and genotoxic stress, often driving metabolic adaptations that amplify NAD production via nicotinamide phosphoribosyltransferase (NAMPT). This endows cancer cells with enhanced proliferative capacity, stress tolerance, and immunoevasive features. Importantly, the dependence of malignant cells on sustained NAD availability constitutes a therapeutically exploitable vulnerability. Accordingly, NAMPT inhibitors, PARP inhibitors, and strategies targeting NAD-consuming ectoenzymes have shown preclinical and, in select settings, clinical efficacy. Here, we critically review the rewiring of NAD metabolism in cancer, associated therapeutic opportunities, and barriers to their clinical exploitation.