Étude du métabolisme des cellules Natural Killer murines en condition basale

Immune cell activation is tightly coupled to metabolic rewiring, yet how specific nutrients support immune effector functions beyond their bioenergetics roles and how their sufficiency is sensed remains incompletely understood. In this study, we uncover a non-redundant role for glucose in murine Natural Killer (NK) cells, where it not only fuels mitochondrial oxidative phosphorylation (OxPhos) but also drives key anabolic pathways essential for effector responses and proliferation. We show that glucose feeds both the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP), which are required for cytokine production, degranulation, and proliferation. Notably, the HBP integrates multiple metabolic inputs—including glucose, glutamine, acetyl-CoA, and ribose—to generate UDP-GlcNAc, the substrate for O-GlcNAcylation. This post-translational modification emerges as a critical nutrient-sensing mechanism, essential for optimal NK cell activation. Mechanistically, O-GlcNAcylation controls mTORC1 activity, establishing a direct link between nutrient availability and this central metabolic checkpoint. In a tumour model of NK cell dysfunction, O-GlcNAcylation is progressively impaired, mirroring the decline of effector functions. Importantly, stimulation with IL-15 restores both O-GlcNAcylation and NK cell activity. Altogether, these findings highlight a previously unappreciated role for glucose in supporting NK cell function and position O-GlcNAcylation as a key integrator of nutrient sensing and antitumour immunity.