The oxidative pentose phosphate pathway breaks down glucose to generate nicotinamide adenine dinucleotide phosphate (NADPH), which is critical for biosynthesis and redox defense in cells. The pathway involves two key NADPH-producing enzymes: glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD). Previous studies have suggested that G6PD supports but PGD limits T cell-mediated immunity. Researchers led by Ludwig Princeton’s Joshua Rabinowitz and Zihong Chen reported in a December issue of PNAS that both enzymes are important for T cell-mediated immune responses. PGD loss in T cells causes systemic depletion of T cells, while G6PD loss results in activation-induced T cell apoptosis. The latter effect cannot be rescued by supplementation with the biosynthetic products of oxidative phosphorylation but could be partially remedied by removal of the oxidized dimeric amino acid cystine from cell culture media. Redox stress induces uptake of cystine, which is normally a precursor to reduced antioxidant molecules like glutathione. But in the absence of sufficient NADPH, the cystine remains stuck in its oxidized dimeric form causing disulfide stress and ultimately apoptosis. The findings establish the pentose phosphate pathway as a driver of anti-tumor immunity and support clinical examination of the efficacy of checkpoint blockade immunotherapies in people with G6PD deficiency—the most common enzyme deficiency in humans.
Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity
PNAS, 2025 December 3