Targeting Nicotinamide Metabolism to Reprogram the Tumor Microenvironment: Mechanisms and Novel Therapeutic Strategies.

The tumor microenvironment (TME) is characterized by heightened metabolic activity, dysfunctional vasculature, and chronic inflammation. Together, these features create an ecosystem that supports tumor progression. This review examines how nicotinamide (NAM) metabolism, mediated through its key enzymes Nicotinamide phosphoribosyl transferase (NAMPT) and Nicotinamide N‑methyltransferase (NNMT), may contribute to malignant remodeling of the TME at three interconnected levels: (1) fueling the hypermetabolic state of cancer cells and contributing to TME acidification; (2) modulating tumor angiogenesis; and (3) establishing and sustaining an immunosuppressive, chronic inflammatory milieu. Building on this framework, we further discuss the therapeutic potential of targeting NAM metabolism-such as via NAM supplementation or inhibition of NAMPT/NNMT-while also addressing challenges like metabolic plasticity. Future research should aim to unravel the dynamic regulation of NAM metabolic networks and their roles in intercellular communication, thereby advancing anticancer strategies from a tumor‑cell‑killing paradigm toward systemic reprogramming of the tumor microenvironment.