细胞内氧化还原（redox）平衡在促进肿瘤进展、发展和治疗抗性方面起着重要作用。因此，氧化还原平衡受损可能成为癌症潜在的治疗靶点。本文开发了一种基于锰的稳态调节剂（MHS），用于诱导严重的活性氧物种积累和谷胱甘肽（GSH）缺乏，其中这种氧化还原失衡导致剧烈的铁死/apoptosis。肿瘤特异性降解锰氧化物纳米载体有助于缓解缺氧并释放载荷，通过增强声动力疗法和化学动力疗法诱导细胞凋亡。另一方面，区域氧合显著下调了活化转录因子4的表达，可以与释放的磺胺嘧啶协同作用，抑制下游半胱氨酸抗体转运蛋白xCT。通过xCT的抑制，谷胱甘肽合成被充分中断，导致谷胱甘肽过氧化物酶4（GPx4）水平降低。产生的过量脂质过氧化物促进强烈的铁死，从而引发细胞死亡。基于这一基础，MHS在体外和体内均展现出辉煌的治疗效果，得益于抗肿瘤免疫的协同作用。综上所述，该范例提供了一种深入抑制铁死/细胞凋亡的治疗策略，并可能扩大锰衍生纳米药物在医学应用中的适用性。本文受版权保护。保留所有权利。

Intracellular redox homeostasis plays an important role in promoting tumor progression, development and even treatment resistance. To this end, redox balance impairment may become a prospective therapeutic target of cancer. Here, a manganese-based homeostasis modulator (MHS) is developed for inducing severe reactive oxygen species accumulation and glutathione (GSH) deprivation, where such redox dyshomeostasis brings about dramatic ferroptosis/apoptosis. Tumor-specific degradation of manganese oxide nanocarriers contributes to hypoxia alleviation and loaded cargo release, resulting in apoptosis by augmented sonodynamic therapy and chemodynamic therapy. On the other hand, regional oxygenation significantly downregulates the expression of activating transcription factor 4, which can synergize with the released sulfasalazine to inhibit the downstream cystine antiporter xCT. Biosynthesis of GSH is sufficiently interrupted by the xCT suppression, leading to the reduction of glutathione peroxidase 4 (GPx4) level. The resultant excessive lipid peroxides promote intense ferroptosis to motivate cell death. On this basis, splendid treatment outcome by MHS is substantiated both in vitro and in vivo, thanks to the synergy of antitumor immunity elicitation. Taken together, this paradigm provides an insightful strategy to evoke drastic ferroptosis/apoptosis toward therapeutics and may also expand the eligibility of manganese-derived nanoagents for medical applications. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.