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Updated: Jul 1, 2025
Analysis of Human Natural Killer Cell Metabolism
Published on: June 22, 2020
Restriction of Glycolysis Increases Serial Killing Capacity of Natural Killer Cells
Lea Katharina Picard1, Jens Alexander Niemann1, Elisabeth Littwitz-Salomon2
1Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), D-44139 Dortmund, Germany.
Abstract:
Tumor cells rely heavily on glycolysis to meet their high metabolic demands. While this results in nutrient deprivation within the tumor microenvironment and has negative effects on infiltrating immune cells such as natural killer (NK) cells, it also creates a potential target for cancer therapies. Here we use Glupin, an inhibitor of glucose transporters, to study the effect of limited glucose uptake on NK cells and their anti-tumor functions. Glupin treatment effectively inhibited glucose uptake and restricted glycolysis in NK cells. However, acute treatment had no negative effect on NK cell cytotoxicity or cytokine production. Long-term restriction of glucose uptake via Glupin treatment only delayed NK cell proliferation, as they could switch to glutaminolysis as an alternative energy source. While IFN-γ production was partially impaired, long-term Glupin treatment had no negative effect on degranulation. Interestingly, the serial killing activity of NK cells was even slightly enhanced, possibly due to changes in NAD metabolism. This demonstrates that NK cell cytotoxicity is remarkably robust and insensitive to metabolic disturbances, which makes cellular metabolism an attractive target for immune-mediated tumor therapies.
Insights
Natural killer (NK) cells show robust anti-tumor functions despite metabolic challenges. Inhibiting glucose uptake in NK cells did not impair their killing ability, highlighting metabolism as a viable cancer therapy target.
Area of Science:
- Immunology
- Metabolic pathways
- Cancer biology
Background:
- Tumor cells heavily utilize glycolysis, leading to nutrient-poor microenvironments.
- This nutrient deprivation negatively impacts immune cells like natural killer (NK) cells.
- Metabolic vulnerabilities in tumors present potential therapeutic targets.
Purpose of the Study:
- To investigate the impact of limited glucose uptake on NK cell anti-tumor functions.
- To assess NK cell responses to Glupin, a glucose transporter inhibitor.
- To explore NK cell metabolic plasticity and its effect on anti-tumor activity.
Main Methods:
- Utilized Glupin, a glucose transporter inhibitor, to restrict glucose uptake in NK cells.
- Assessed NK cell cytotoxicity, cytokine production (IFN-γ), proliferation, and degranulation.
- Evaluated the effects of both acute and long-term Glupin treatment.
Main Results:
- Glupin effectively inhibited NK cell glucose uptake and glycolysis.
- Acute Glupin treatment did not affect NK cell cytotoxicity or cytokine production.
- Long-term treatment only delayed proliferation, with NK cells switching to glutaminolysis.
- IFN-γ production was partially impaired, but degranulation remained unaffected.
- Serial killing activity of NK cells was slightly enhanced.
Conclusions:
- NK cell anti-tumor functions, particularly cytotoxicity, are remarkably robust against metabolic disturbances.
- NK cells exhibit metabolic plasticity, utilizing glutaminolysis when glucose is limited.
- Targeting cellular metabolism is a promising strategy for immune-mediated cancer therapies.
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