Abstract
There are many strategies to harness the immune system against infections and cancer, ranging from antibodies to checkpoint inhibitors to adoptive cell therapies. In recent years, natural killer (NK) cells have emerged as a particularly promising tool because of their ability to destroy infected or transformed cells without prior sensitization. However, their effectiveness depends heavily on their metabolic health, and until now, little was known about the role of fatty acid oxidation (FAO) in supporting NK cell function. In 2024, Sheppard and colleagues published a study in Proceedings of the National Academy of Sciences revealing that FAO, specifically through the enzyme CPT1A, is a critical energy pathway that fuels NK cell responses during both infection and cancer.
What are Natural Killer Cells?
NK cells are part of the innate immune system, acting as rapid responders that kill target cells and secrete cytokines to recruit other immune defenses. To carry out these tasks, they require substantial energy. While NK cells have been known to rely on aerobic glycolysis, the researchers hypothesized that the fatty acid–rich environments present in certain infections and tumors might provide an alternative fuel source. They focused on CPT1A, an enzyme that transports long-chain fatty acids into the mitochondria for oxidation, and investigated its role in NK cell activity.
Using mouse models of viral infection and cancer, the researchers found that NK cells activated by either murine cytomegalovirus or tumor challenge took up significantly more fatty acids and expressed higher levels of CPT1A than NK cells from uninfected mice. This pattern was also observed in NK cells from patients with acute myeloid leukemia. To test whether this fatty acid metabolism was essential, they engineered mice whose NK cells lacked CPT1A. These NK cells showed reduced mitochondrial activity, impaired use of fatty acids in the tricarboxylic acid (TCA) cycle, and diminished production of critical metabolites like aspartate. Functionally, the CPT1A-deficient NK cells proliferated less, expanded poorly in response to infection, and were less capable of killing target cells. They also formed fewer actin rings at the immune synapse, structures essential for delivering lethal hits, and failed to control melanoma metastases in mouse lungs.
Fatty Acid Oxidation Effects
These findings highlight fatty acid oxidation as a vital metabolic axis for NK cell performance. In nutrient-limited or hostile tumor environments, FAO enables NK cells to maintain mitochondrial energy production, support sustained proliferation, and preserve cytotoxicity. This has clear implications for NK cell–based therapies. By optimizing FAO during NK cell manufacturing, scientists could create more resilient therapeutic cells. Likewise, drugs that enhance CPT1A function might boost NK responses in cancer or chronic infection, whereas treatments that block FAO could inadvertently weaken innate immunity.
Like any emerging discovery, these insights raise new questions. NK cells may switch to other metabolic fuels in different disease settings, so it is important to determine how universal FAO’s role is across cancer types and infectious contexts. Moreover, targeting CPT1A therapeutically would require balancing the metabolic needs of NK cells with potential side effects in other tissues. Clinical translation will also require testing whether enhancing FAO in NK cells improves their performance in human patients, and whether tumor microenvironments with high lipid content can be exploited to NK cells’ advantage.
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