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<p>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.</p>

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Metabolic reprogramming of myeloid cells in cancer: from lactate–NAMPT axis to AI-guided therapeutics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • In-Gu Lee,
  • Keehoon Jung

摘要

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.