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<p>In their recent study, Jedlička et al. demonstrate that glutaminase (GLS) activity is indispensable for sustaining human natural killer (NK) cell cytotoxicity, positing it as a key metabolic regulator of effector function. While this work provides a valuable foundation for understanding NK cell immunometabolism, our analysis identifies several critical areas requiring deeper exploration. This letter offers a prospective critique, highlighting the incomplete delineation of the downstream metabolic mechanisms—specifically regarding energy production, biosynthetic precursor synthesis, and redox homeostasis—that link GLS activity to the cytolytic machinery. Furthermore, we question the physiological relevance of these in vitro findings within the nutrient-deprived and competitive tumor microenvironment (TME), where NK cells must exhibit metabolic flexibility. A paramount concern is the translational double-edged sword of GLS inhibition, which may inadvertently suppress anti-tumor immunity. We conclude that future research must employ integrated multi-omics and in vivo models to resolve these complexities, which is essential for harnessing NK cell metabolism without compromising its therapeutic potential.</p>

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Glutaminase as a metabolic checkpoint in NK cell cytotoxicity: mechanistic uncertainties and translational implications

  • 期刊论文

  • 发表日期：

    2025年11月13日

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  • DuJiang Yang,
  • GuoYou Wang

摘要

In their recent study, Jedlička et al. demonstrate that glutaminase (GLS) activity is indispensable for sustaining human natural killer (NK) cell cytotoxicity, positing it as a key metabolic regulator of effector function. While this work provides a valuable foundation for understanding NK cell immunometabolism, our analysis identifies several critical areas requiring deeper exploration. This letter offers a prospective critique, highlighting the incomplete delineation of the downstream metabolic mechanisms—specifically regarding energy production, biosynthetic precursor synthesis, and redox homeostasis—that link GLS activity to the cytolytic machinery. Furthermore, we question the physiological relevance of these in vitro findings within the nutrient-deprived and competitive tumor microenvironment (TME), where NK cells must exhibit metabolic flexibility. A paramount concern is the translational double-edged sword of GLS inhibition, which may inadvertently suppress anti-tumor immunity. We conclude that future research must employ integrated multi-omics and in vivo models to resolve these complexities, which is essential for harnessing NK cell metabolism without compromising its therapeutic potential.