The study investigates the role of fatty acid oxidation (FAO) in natural killer (NK) cells, which are crucial for immune surveillance against infections and cancer. The research finds that activated NK cells increase their uptake of fatty acids and express the enzyme carnitine palmitoyltransferase I (CPT1A), which is essential for long-chain fatty acid oxidation. Using a mouse model with a specific deletion of CPT1A in NK cells, the authors observe reduced mitochondrial function and impaired aspartate production. Additionally, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. These findings highlight the importance of FAO in maintaining NK cell metabolic resilience and suggest that optimizing FAO in NK cells could enhance their effectiveness in immunotherapies.The study investigates the role of fatty acid oxidation (FAO) in natural killer (NK) cells, which are crucial for immune surveillance against infections and cancer. The research finds that activated NK cells increase their uptake of fatty acids and express the enzyme carnitine palmitoyltransferase I (CPT1A), which is essential for long-chain fatty acid oxidation. Using a mouse model with a specific deletion of CPT1A in NK cells, the authors observe reduced mitochondrial function and impaired aspartate production. Additionally, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. These findings highlight the importance of FAO in maintaining NK cell metabolic resilience and suggest that optimizing FAO in NK cells could enhance their effectiveness in immunotherapies.