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The term NADome refers to the intricate network of intracellular and extracellular enzymes that regulate the synthesis or degradation of nicotinamide adenine dinucleotide (NAD) and to the receptors that engage it. Traditionally, NAD was linked to intracellular energy production through shuffling electrons between oxidized and reduced forms. However, recent data indicate that NAD, along with its biosynthetic and degrading enzymes, has a life outside of cells, possibly linked to immuno-modulating non-enzymatic activities. Extracellular NAD can engage puriginergic receptors triggering an inflammatory response, similar - to a certain extent – to what described for adenosine triphosphate (ATP). Likewise, NAD biosynthetic and degrading enzymes have been amply reported in the extracellular space, where they possess both enzymatic and non-enzymatic functions. Modulation of these enzymes has been described in several acute and chronic conditions, including obesity, cancer, inflammatory bowel diseases and sepsis. In this review, the role of the extracellular NADome will be discussed, focusing on its proposed role in immunomodulation, together with the different strategies for its targeting and their potential therapeutic impact.

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.

Cancer cells, particularly in solid tumors, are surrounded by non-neoplastic elements, including endothelial and stromal cells, as well as cells of immune origin, which can support tumor growth by providing the right conditions. On the other hand, local hypoxia, and lack of nutrients induce tumor cells to reprogram their metabolism in order to survive, proliferate, and disseminate: the same conditions are also responsible for building a tumor-suppressive microenvironment. In addition to tumor cells, it is now well-recognized that metabolic rewiring occurs in all cellular components of the tumor microenvironment, affecting epigenetic regulation of gene expression and influencing differentiation/proliferation decisions of these cells. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor for energy transduction in metabolic processes. It is also a key component of signaling pathways, through the regulation of NAD-consuming enzymes, including sirtuins and PARPs, which can affect DNA plasticity and accessibility. In addition, both NAD-biosynthetic and NAD-consuming enzymes can be present in the extracellular environment, adding a new layer of complexity to the system. In this review we will discuss the role of the “NADome” in the metabolic cross-talk between cancer and infiltrating immune cells, contributing to cancer growth and immune evasion, with an eye to therapeutic implications.