The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Kunkemoeller, B., Prendeville, H. et al. Nature Metabolism. 7: 1630–1645. (2025).
doi: 10.1038/s42255-025-01330-w.
doi: 10.1038/s42255-025-01330-w.
Summary of the findings
Summary of the findingsObesity is a major risk factor for many cancers. This is due in part to defective anti-tumour immune responses, caused by changes in systemic and cellular metabolism. While mouse models of diet induced obesity have revealed many mechanisms of immune dysfunction in obesity, most studies use only one fat source – lard. In this study, we examined how different dietary lipids impact tumour growth and shape the anti-tumour immune response in obesity.
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To test this, mice were fed high-fat diets (HFD) derived from a variety of fat sources and later injected with B16 melanoma cells. While all HFDs resulted in significant weight gain, we found that tumour growth kinetics were dependent on the source of dietary fat. Tumours grew rapidly in mice fed butter-HFD but not mice fed palm oil-HFD, which had a similar growth pattern to mice fed a standard fat diet. These differences were reflected in the tumour immune landscape, where infiltration of Natural Killer (NK) cells was significantly reduced in mice fed butter-HFD, but not palm oil-HFD. Furthermore, IFNγ production by NK and CD8 T cells was defective in mice fed butter-HFD but not palm oil-HFD. These differences were driven by distinct effects on the plasma metabolome and intracellular metabolism. We identified stearoyl-carnitine (CAR18:0) as an immunosuppressive lipid metabolite enriched in the plasma of mice fed butter-HFD. CAR18:0 induced mitochondrial dysfunction and impaired IFNγ production in CD8 T cells, which blunted their cytotoxicity. While NK cells were resistant to the effects of CAR18:0, NK cells from mice fed butter-HFD accumulated intracellular lipids and could not elevate the rates of cellular metabolism in response to cytokine. Conversely, NK cells from mice fed palm oil-HFD maintained optimal lipid homeostasis and were protected from metabolic dysfunction, possibly through sustained cMyc activity.
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Future impact
Our work demonstrates that diet shapes the anti-tumour immune response in obesity. Modifying dietary fat presents an affordable and promising strategy to improve cancer outcomes in obesity, by adjusting the metabolic milieu to promote an effective anti-tumour immune response. Future investigations may focus on the role of diet in the context of immunotherapy and may reveal particular dietary components or metabolites that maximise the benefits of immunotherapy.
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