Abstract Myeloid cells—including macrophages, monocytes, neutrophils and dendritic cells—are metabolically plastic sentinels that shape the tumor microenvironment. Among the myriad metabolites in cancer, lactate and nicotinamide adenine dinucleotide (NAD⁺) stand out as central coordinators of myeloid cell fate. Lactate accumulation, driven by tumor glycolysis, profoundly reprograms myeloid metabolism through receptor-mediated signaling, monocarboxylate transport and histone lactylation, establishing immunosuppressive and pro-angiogenic phenotypes. Parallel to this, the nicotinamide phosphoribosyltransferase (NAMPT)-dependent NAD⁺ salvage pathway sustains redox homeostasis and epigenetic regulation in myeloid cells, controlling sirtuin-mediated deacetylation and transcriptional rewiring. Emerging evidence suggests a lactate–NAMPT feedback circuit that couples extracellular lactate availability with intracellular NAD⁺ turnover to maintain immunoregulatory states within tumors. In this Review, we integrate current knowledge on lactate metabolism and NAMPT signaling in tumor-associated myeloid cells, highlighting their convergence on metabolic and epigenetic checkpoints. We further discuss how artificial intelligence (AI)—through single-cell multi-omics integration, spatial metabolomic inference and graph-based modeling—can decode complex immunometabolic networks and accelerate drug discovery targeting these pathways. Finally, we outline therapeutic strategies combining lactate-targeting agents, NAMPT inhibitors and immunotherapies, emphasizing the promise of AI-guided precision immunometabolism. Understanding and modeling the lactate–NAMPT axis may unlock new avenues to reprogram myeloid immunity and overcome resistance in cancer therapy.
Lee et al. (2026) studied this question.