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谷胱甘肽代谢失调损害急性白血病患者的 NK 细胞功能

英文原题：Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia.

查看英文原题

Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia.

PubMed 2025/04/03（内容时间） Int Immunopharmacol Q1 · IF 5.6（JCR 2025）

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技术：NK 细胞白血病地区：中国
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中文摘要

急性白血病患者的自然杀伤（NK）细胞功能显著受损，削弱了抗肿瘤免疫应答。然而，NK 细胞功能障碍的潜在机制尚未完全阐明。

本研究发现，急性白血病患者来源 NK 细胞（AL-NK）胞内谷胱甘肽（GSH）水平显著降低，同时氧化还原稳态受损、线粒体活性氧水平升高。流式细胞术和转录组分析表明，GSH 代谢失调导致 NK 细胞线粒体功能障碍，进而损害其抗白血病细胞毒性和增殖能力。

值得注意的是，补充还原型谷胱甘肽乙酯（GSHEE，GSH 前体）可有效恢复 AL-NK 细胞 GSH 水平，增强线粒体活性、氧化磷酸化和 ATP 生成，并提高 NK 细胞介导的细胞毒性。

此外，GSHEE 处理可激活 NK 细胞中的 mTOR 信号通路，进一步促进其功能和增殖。总体而言，本研究确定 GSH 代谢失调是急性白血病 NK 细胞功能障碍的关键驱动因素，并提示基于 GSH 的干预可能成为增强 NK 细胞免疫疗法的有前景策略。

展开英文摘要原文

Natural killer (NK) cell function is markedly impaired in patients with acute leukemia, weakening their anti-tumor immune response.

However, the mechanisms underlying NK cell dysfunction are not fully understood.

Here, we reveal that NK cells from patients with acute leukemia (AL-NK) exhibit significantly reduced intracellular glutathione (GSH) levels, accompanied by disrupted redox homeostasis and increased levels of mitochondrial reactive oxygen species. Flow cytometry and transcriptomic analyses indicate that dysregulated GSH metabolism leads to mitochondrial dysfunction in NK cells, thereby impairing their antileukemic cytotoxicity and proliferative capacity.

Notably, supplementation with glutathione reduced ethyl ester (GSHEE)-a GSH precursor-effectively restores GSH levels in AL-NK cells, enhancing mitochondrial activity, oxidative phosphorylation, ATP production, and NK cell-mediated cytotoxicity.

Moreover, GSHEE treatment activates the mTOR signaling pathway in NK cells, further promoting their function and proliferation.

Overall, our study identifies dysregulated GSH metabolism as a key driver of NK cell dysfunction in acute leukemia and suggests that GSH-based interventions may provide a promising strategy to enhance NK cell-mediated immunotherapies.

论文信息

作者
Zhao Y、Wang Y、Liang T、Song X、Zhu Y、Liu X、Lv M、Zheng C
第一作者单位
Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230022, China.China
通讯作者单位
Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230022, China. Electronic address: fangni@ustc.edu.cn.China
期刊
International immunopharmacology2025 May 8
原文标识
PubMed 40184815　·　DOI 10.1016/j.intimp.2025.114566

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