据报道，许多癌症中葡萄糖代谢增强。 6-磷酸葡萄糖脱氢酶 (G6PD) 是一种参与磷酸戊糖途径的限速酶，可维持 NADPH 水平并保护细胞免受氧化损伤。我们最近发现低 G6PD 表达与活跃的肿瘤免疫相关。然而，涉及G6PD和肿瘤免疫的机制仍不清楚。我们使用G6PD敲低的恶性黑色素瘤细胞进行了体外研究，使用GEO数据集进行了通路分析，使用小鼠黑色素瘤模型与免疫检查点抑制剂（ICIs）联合进行了体内研究以及对接受 ICI 治疗的 42 名黑色素瘤患者和 30 名肺癌患者进行的预后分析。化学和基因上的 G6PD 抑制已被证明可以减少 NADPH 的产生并降低其氧化应激耐受性。这导致细胞死亡，并伴随着高迁移率族盒 1 的释放和钙网蛋白易位至质膜。这些发现表明，抑制 G6PD 可以诱导免疫原性细胞死亡。在移植 G6PD 敲低 B16 黑色素瘤细胞并用抗 PD-L1 抗体治疗的 C57BL/6 小鼠实验中，观察到肿瘤大小显着减小。有趣的是，仅在部分病变中抑制G6PD会增加其他病变对ICI的敏感性。此外，在接受 ICI 治疗的 42 名黑色素瘤患者和 30 名肺癌患者中，低 G6PD 表达的患者比 G6PD 高表达的患者预后更好（p=0.0473；黑色素瘤，p=0.0287；肺癌）。触发肿瘤中免疫原性细胞死亡的有效治疗策略，显着增强免疫疗法的功效。©作者（或其雇主）2024。在 CC BY-NC 下允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Enhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear.We conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs.Inhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer).G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.