NAD+ as a metabolic immune checkpoint in cancer

Nicotinamide adenine dinucleotide (NAD+) functions in cancer as a compartmentalized signaling currency, coupling tumor cell fitness to immune competence within the tumor microenvironment (TME). In malignant cells, NAD+ sustains redox balance, poly(ADP-ribose) polymerase (PARP)-dependent DNA repair, sirtuin-mediated chromatin remodeling, and metabolic stress adaptation. In immune effector cells, the same metabolite governs mitochondrial integrity, effector persistence, and resistance to exhaustion. This duality is the basis of the explanation advanced here for why first-generation inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting salvage pathway enzyme, failed clinically when deployed as cytotoxic monotherapies without an immunometabolic rationale. This review synthesizes the field around a central premise: NAD+ operates as a context-dependent metabolic immune checkpoint whose therapeutic value depends on where in the tumor immune ecosystem the pathway is perturbed and whether checkpoint blockade is deployed concurrently. The therapeutic landscape is reorganized around five pharmacological classes, which differ in how far each has been tested: (i) NAMPT catalytic inhibitors, evaluated clinically and withdrawn; (ii) bifunctional NAMPT/programmed death-ligand (PD-L1) compounds and proteolysis-targeting chimera (PROTAC)-mediated NAMPT degradation, both preclinical; (iii) NAD+ precursor-based immunorestorative strategies, including ex vivo rescue of age-associated chimeric antigen receptor T (CAR-T) cell dysfunction through NMN/CD38 inhibitor combinations; (iv) adenosinergic axis targeting, in which anti-CD38 and anti-CD73 agents are approved or in trials while the proposed triple-blockade of CD38, CD73, and PD-1/PD-L1 remains untested; and (v) combinations with PARP and indoleamine 2,3-dioxygenase (IDO) inhibitors, which rest on mechanistic rationale. A tripartite pharmacological taxonomy distinguishes intracellular (iNAMPT), extracellular (eNAMPT), and vesicle-associated (vNAMPT) NAMPT as discrete drug targets. The analyses examines how TME acidification, precursor competition, and extracellular NAD+ catabolism through the CD38–CD203a–CD73 noncanonical adenosine axis reshape immune fitness, and why biomarker-guided separation of tumor-directed NAD+ depletion from immune-directed NAD+ restoration is required for rational clinical translation. Throughout, findings that are experimentally established are separated from those that remain contested or hypothetical, and the criteria under which the checkpoint designation is analytically useful, together with the conditions under which it is not, are stated explicitly.