CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor
Ishita Sarkar, Debashree Basak, Puspendu Ghosh, Anupam Gautam, Arpita Bhoumik, Praveen Singh, Anwesha Kar, Shaun Mahanti, Snehanshu Chowdhury, Lagnajita Chakraborty, Soumya Mondal, Ramanuj Mukherjee, Shikhar Mehrotra, Saikat Majumder, Shantanu Sengupta, Sandip Paul, Shilpak Chatterjee
Abstract
In the tumor microenvironment (TME), regulatory T cells (T regs ) 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 T regs by inducing hypermethylation at the Foxp3 locus. Restoring NAD + with nicotinamide mononucleotide reverses this adaptation, pushing T regs back to the TCA cycle and reducing their suppressive function. In YUMM1.7 melanoma-bearing mice, small-molecule CD38 inhibition selectively destabilizes intratumoral T regs , sparking robust antitumor immunity. These findings reveal that targeting the CD38-NAD + axis disrupts T regs metabolic adaptation and offers a strategy to enhance antitumor responses.