Altered nutrient availability and metabolite levels in the cancer microenvironment can impact on immune cell function. Natural killer (NK) cells are important anti-tumour effector cells that can respond rapidly to destroy malignant cells and are a key component in the biological response to monoclonal antibody-based therapies, by engaging in antibody-dependent cell-mediated cytotoxicity. In many cases, however, NK cells become dysfunctional in cancer. It is currently unknown whether metabolic stress in NK cells leads to, or contributes to, reduced anti-tumour activity. The metabolic profile of NK cells is distinct from other lymphocyte populations, having higher lipid uptake and storage capacity compared with that of B cells, and various T cell populations. In Eµ-myc lymphoma-bearing mice we show that NK cells display functional defects, particularly loss of IFN gamma production, which is paralleled by substantial changes to cellular metabolism. NK cells have defective glycolysis and OXPHOS, mTOR pathway activation and decreased mitochondrial function. We hypothesized that the functional and metabolic defects of NK cells in lymphoma are due to chronic exposure to elevated circulating fatty acids (FA) that were observed in this lymphoma model. Supplying NK cells with high levels of FA in vitro suppressed cytokine-induced production of IFN-g and granzyme B, proliferation, and phosphorylation of S6, mimicking the effects in vivo. Outcomes of this ongoing work will identify metabolic defects within NK cells caused by nutrient excess in the lymphoma environment, which could be targeted to reprogram NK cell metabolism and restore anti-tumour activity.