Identification of serine as an essential amino acid for human NK cell effector functions 3897

Abstract Description Natural killer (NK) cells are innate lymphoid cells with potent antitumor function. Upon cytokine stimulation, NK cells undergo dramatic metabolic reprogramming to provide energy and biomolecules for increased proliferation, production of inflammatory cytokines, and cytotoxicity. However, the global metabolic adaptations induced in cytokine-activated human NK cells are poorly understood. To address this, we performed unbiased metabolomics on naïve and IL-2/15-stimulated primary human NK cells and identified an enrichment in serine/glycine metabolic processes upon activation. Ex vivo serine restriction of human NK cells prevented cytokine-induced upregulation of glucose metabolism, mitochondrial respiration, and mTOR signaling, leading to impaired effector function. Comprehensive isotope-labeled serine tracing indicated that serine contributes to sphingolipid and one carbon metabolism, and tuning glutathione synthesis with CRISPR was sufficient to skew NK cells toward inflammatory or cytotoxic profiles. Glucose tracing revealed that human NK cells fail to synthesize serine de novo due to absent expression of the serine synthesis enzyme PHGDH. CRISPR activation-mediated overexpression of PHGDH in human NK cells restored function and synergized with dietary serine restriction in vivo to control solid tumor growth. These findings identify serine as a key mediator of human NK cell metabolic reprogramming and show that engineering serine metabolism can enhance NK cell therapy. Funding Sources Supported by NIH R01AI145997, R01AI174519, T32GM008042, T32GM152342, T32AI007323, and 1F30AI181449-01. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)