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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 619
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alone decreased tumor volume and increased CD8 T cell production of IFNg and, together with anti-PD-1,
[96]
elicited a more robust anti-tumor effect in murine mammary carcinoma tumors .
Collectively, these data strongly demonstrate that tumor-derived adenosine has detrimental effects on CD8
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T cell infiltration and effector functions, thereby contributing to anti-PD-1/PD-L1 resistance mechanisms.
As such, there is a compelling need for the continued development of adenosine-targeting drugs that can
synergize with current anti-PD-1/PD-L1 therapies to prevent resistance and evoke better patient response.

NAD +
NAD is comprised of adenosine monophosphate linked to nicotinamide mononucleotide. NAD can be
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reduced to form NADH or phosphorylated and subsequently reduced to form NADP or NADPH,
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respectively. NAD is synthesized through three pathways: de novo biosynthesis, Preiss-Handler pathway,
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[97]
or the salvage pathway, the latter of which is the predominant way that cells restore NAD levels
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[Figure 1]. NAD is a co-factor that is involved in a variety of redox and non-redox reactions. In energy
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metabolism, NAD and its derivatives are indispensable for cellular function because they accept and donate
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electrons in a variety of metabolic pathways, such as glycolysis, pentose phosphate pathway, TCA cycle, and
fatty acid b-oxidation . NAD also acts as a substrate for multiple enzyme families, including sirtuins,
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[98]
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[97]
PARPs, and ADP-ribosyl cyclases . Moreover, the metabolic pathways of adenosine and NAD are tightly
linked through CD38, an ectoenzyme present on the surface of tumor and immune cells, which depletes
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[99]
NAD levels, which ultimately results in adenosine formation .
High NAD levels are required in malignant cells to meet their increased energetic demands for rapid
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growth and proliferation. Therefore, malignant cells will upregulate NAD biosynthesis to replenish
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intracellular stores, leading to depletion of this metabolite within the TIME. Several enzymes involved in
anabolic NAD pathways, such as nicotinamide phosphoribosyltransferase (NAMPT), have been heavily
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[100]
implicated in cancer progression and severity . Moreover, drugs targeting these enzymes have shown
promising results in pre-clinical and clinical studies . Targeting tumor-intrinsic NAD metabolism is a
[101]
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promising therapeutic approach because it would restore NAD levels in the TIME, thus allowing T cells to
utilize this metabolite to maintain proper function.
NAD is highly important for anti-tumor immune functions and NAMPT is an important regulator of
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NAD availability. As previously mentioned, NAD and adenosine metabolism are highly linked due to the
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ability of NAD to be converted to adenosine. Inhibiting NAMPT in tumor cells reduces levels of
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[102]
intracellular NAD and extracellular adenosine, thereby enhancing CD8 T cell functions . Further,
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NAMPT expression in CD8 T cells is necessary to produce NAD and induce anti-tumor effects . In
[103]
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tumor-infiltrating lymphocytes (TILs), NAMPT and NAD levels are lower compared to peripheral T
cells , suggesting that the TIME induces NAD depletion in TILs, leading to impaired function.
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[103]
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Mechanistically, NAD deficiency in TILs drives mitochondrial dysfunction and reduces ATP production,
whereas supplementation with nicotinamide (NAM), the substrate of NAMPT, reverses these effects to
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promote a strong anti-tumor immune response in vivo . Interestingly, TCR stimulation in CD8 T cells
[103]
leads to a 16-fold upregulation of NAMPT, compared to 1.3-fold upregulation in Tregs . This suggests
[104]
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that CD8 T cells rely more heavily on NAMPT expression and NAD levels compared to Tregs, giving these
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immunosuppressive cells an advantage in the NAD -depleted TIME. Consistently, Tregs are particularly
sensitive to NAD -induced cell death , and systemic NAD treatment preferentially depleted Tregs,
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[105]
[106]
leading to decreased tumor volume . To date, there are several pre-clinical and clinical studies
investigating the use of NAMPT inhibitors in both solid and hematologic malignancies . However,
[107]
systemic inhibition of NAMPT might have profound adverse effects on CD8 T cell function, decreasing the
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drugs’ efficacy. Perhaps these types of drugs are more effective in cancers that do not have high T cell
infiltration but overexpress NAMPT.