Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Em-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrialmembrane potential and IFN-γ production.Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.