Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), D-44139 Dortmund, Germany.
Institute for Virology, Institute for Translational HIV Research, University Hospital Essen, D-45147 Essen, Germany.
Int J Mol Sci. 2024 Mar 2;25(5):2917. doi: 10.3390/ijms25052917.
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.
肿瘤细胞严重依赖糖酵解来满足其高代谢需求。虽然这导致肿瘤微环境中的营养物质匮乏，并对浸润的免疫细胞（如自然杀伤（NK）细胞）产生负面影响，但它也为癌症治疗提供了一个潜在的靶点。在这里，我们使用葡萄糖转运蛋白抑制剂 Glupin 来研究有限的葡萄糖摄取对 NK 细胞及其抗肿瘤功能的影响。Glupin 处理有效地抑制了 NK 细胞的葡萄糖摄取和糖酵解。然而，急性处理对 NK 细胞的细胞毒性或细胞因子产生没有负面影响。通过 Glupin 处理长期限制葡萄糖摄取仅延迟了 NK 细胞的增殖，因为它们可以转向谷氨酰胺分解作为替代能源。虽然 IFN-γ 的产生部分受损，但长期 Glupin 处理对脱粒没有负面影响。有趣的是，NK 细胞的连续杀伤活性甚至略有增强，这可能是由于 NAD 代谢的变化。这表明 NK 细胞的细胞毒性非常强大，并且对代谢紊乱不敏感，这使得细胞代谢成为免疫介导的肿瘤治疗的一个有吸引力的靶点。
