尽管最近对恶性黑素瘤进行的靶向治疗和免疫治疗令人鼓舞，但大多数患者会产生耐药性，说明有必要确定其他药物靶点以改善疗效。最近，人们开始关注调节氧化还原平衡的途径，特别是保护细胞免受铁死亡的脂质过氧化途径。在这里，我们发现微粒体谷胱甘肽S转移酶1（MGST1），一种非硒依赖性谷胱甘肽过氧化物酶，在恶性黑素瘤和耐药性黑素瘤中高度表达，并作为转移能力和治疗敏感性的特定决定因子。小鼠和人黑素瘤中MGST1的缺失增强了细胞氧化应激，减弱了糖酵解、氧化磷酸化和戊糖磷酸途径。gp100激活的pmel-1 T细胞杀死了更多的Mgst1 KD而不是对照黑素瘤细胞，而KD细胞对细胞毒性抗癌药和铁死细胞死亡更敏感。与对照组相比，携带Mgst1 KD B16肿瘤的小鼠中有更多的CD8+ T细胞浸润，抑制性受体表达减少，细胞因子反应增强，肺转移大幅减少，生存期延长。靶向MGST1可以改变氧化还原平衡，限制黑素瘤的转移，增强化疗和免疫治疗的治疗指数。版权所有 © 2023. 由Elsevier Ltd. 发布。

While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets to improve outcomes. Recently, attention has been given to pathways that regulate redox homeostasis, especially the lipid peroxidase pathway that protects cells against ferroptosis. Here we identify microsomal glutathione S-transferase 1 (MGST1), a non-selenium-dependent glutathione peroxidase, as highly expressed in malignant and drug resistant melanomas and as a specific determinant of metastatic spread and therapeutic sensitivity. Loss of MGST1 in mouse and human melanoma enhanced cellular oxidative stress, and diminished glycolysis, oxidative phosphorylation, and pentose phosphate pathway. Gp100 activated pmel-1 T cells killed more Mgst1 KD than control melanoma cells and KD cells were more sensitive to cytotoxic anticancer drugs and ferroptotic cell death. When compared to control, mice bearing Mgst1 KD B16 tumors had more CD8+ T cell infiltration with reduced expression of inhibitory receptors and increased cytokine response, large reduction of lung metastases and enhanced survival. Targeting MGST1 alters the redox balance and limits metastases in melanoma, enhancing the therapeutic index for chemo- and immunotherapies.Copyright © 2023. Published by Elsevier Ltd.