Abstract
In the tumor microenvironment (TME), regulatory T cells (Tregs) adapt their metabolism to thrive in low-glucose, high-lactate conditions, but the mechanisms remain unclear. Our study identifies CD38 as a key regulator of this adaptation by depleting nicotinamide adenine dinucleotide (oxidized form) (NAD+), redirecting lactate-derived pyruvate toward phosphoenolpyruvate and bypassing the tricarboxylic acid (TCA) cycle. This prevents accumulation of α-ketoglutarate, which destabilizes Tregs by inducing hypermethylation at the Foxp3 locus. Restoring NAD+ with nicotinamide mononucleotide reverses this adaptation, pushing Tregs back to the TCA cycle and reducing their suppressive function. In YUMM1.7 melanoma-bearing mice, small-molecule CD38 inhibition selectively destabilizes intratumoral Tregs, sparking robust antitumor immunity. These findings reveal that targeting the CD38-NAD+ axis disrupts Tregs metabolic adaptation and offers a strategy to enhance antitumor responses.