Macrophages tune NK cell IFNγ production through direct lipid transfer

Abstract

Abstract Natural killer (NK) cells are critical effectors of innate immunity, but their activity is strongly influenced by metabolic state. While intrinsic NK metabolism has been studied extensively, less is known about how surrounding immune cells shape NK cell function. Here, we identify a direct metabolic communication axis between macrophages and NK cells. Using co-culture and in vivo models, we show that lipopolysaccharide-stimulated macrophages induce lipid accumulation in NK cells that suppresses mTORC1 activity and the production of IFNγ. This lipid accumulation is visualised as increased lipid droplets content in NK cells, generated using fatty acids synthesised within the macrophages. Genetic and pharmacological approaches show that fatty acid transfer from macrophages to NK cells requires cell-cell contact and is associated with CD36 protein transfer via trogocytosis. Blocking fatty acid synthesis specifically in macrophages prevents lipid accumulation in NK cells and restores both mTORC1 activity and IFNγ production. These findings define a previously unrecognized mechanism of macrophage-NK cell cross-regulation, revealing how metabolic exchange constrains NK effector function and establishing a feedback circuit with implications for hyperinflammation and immunotherapy.