NAMPT beyond NAD+ biosynthesis: roles in tumor microenvironment remodeling and cancer progression.

The tumor microenvironment (TME) is characterized by chronic inflammation, high metabolic activity, and aberrant vascular function, which together create an ecosystem that supports tumor progression. In this review, we summarize the multifaceted pro-tumorigenic mechanisms through which nicotinamide phosphoribosyltransferase (NAMPT) regulates key features of the TME, including macrophage polarization and immune responses, metabolic reprogramming and TME acidification, angiogenesis, and the maintenance of epithelial-mesenchymal transition and cancer stemness. These interconnected processes collectively shape TME evolution and promote malignant progression. We also integrate recent structural insights into NAMPT catalytic architecture and ligand-bound inhibitory and activating complexes, highlighting the structural basis for NAMPT druggability. We further discuss recent advances in therapeutic strategies targeting NAMPT in cancer, including natural products, small-molecule inhibitors, and RNA-based approaches, and we highlight current challenges and future directions in the field. A deeper understanding of the complex roles of NAMPT in the TME will be essential for shifting anticancer therapy from direct tumor cell killing toward systemic reprogramming of the tumor ecosystem.