先前的研究发现，活化的CD8+ T细胞分泌升高的干扰素γ（IFN-γ）以触发肿瘤细胞的铁死亡。然而，由于在免疫抑制的肿瘤微环境中CD8+ T细胞分泌干扰素γ较少，因此IFN-γ介导的铁死亡在肿瘤细胞中仅能以较低水平诱导。最近的研究表明，锰离子可以激活环状鸟苷酸单磷酸腺苷酸合成酶/干扰素基因刺激器（cGAS-STING）途径并支持针对肿瘤的适应性免疫反应，增强肿瘤浸润性CD8+ T细胞的水平。因此，设计了肿瘤微环境响应的基于锰的纳米酶（Mn-based NEs），用于激活cGAS-STING途径以放大免疫驱动的铁死亡。这个多功能的全一体纳米平台是通过锰3+离子和3,3'-二硫基丙酸之间的配位简单而温和地合成的。经过细胞内传递后，Mn-based NEs的每个组分都发挥其功能。也就是说，谷胱甘肽通过二硫键-巯基交换和Mn3+ /Mn2+的氧化还原对被消耗，通过类Fenton反应产生羟基自由基（·OH）来引发铁死亡，Mn2+增强cGAS-STING活性以推动免疫驱动的铁死亡。此外，铁死亡放大了Mn2+诱导的免疫原性细胞死亡并启动了抗肿瘤免疫“闭环”，以及免疫驱动的铁死亡。值得注意的是，这种多功能纳米平台在杀死初级和远端肿瘤方面都非常有效。©2023 Wiley-VCH GmbH。

Previous studies have found that activated CD8+ T cells secrete elevated levels of interferon-gamma (IFN-γ) to trigger ferroptosis in tumor cells. However, IFN-γ-mediated ferroptosis is induced at low levels in tumor cells because of the limited IFN-γ secreted by CD8+ T cells in the immunosuppressive tumor microenvironment. Recent studies have shown that manganese ion can activate the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase/stimulator of interferon genes (cGAS-STING) pathway and support adaptive immune responses against tumors, which enhances the level of tumor-infiltrating CD8+ T cells. Therefore, tumor microenvironment-responsive Mn-based nanoenzymes (Mn-based NEs) that activated the cGAS-STING pathway are designed to amplify immune-driven ferroptosis. The multifunctional all-in-one nanoplatform is simply and mildly synthesized by the coordination between Mn3+ ions and 3,3'-dithiodipropionic acid. After intracellular delivery, each component of Mn-based NEs exerts its function. That is, glutathione is depleted through disulfide-thiol exchange and redox pair of Mn3+ /Mn2+ , a hydroxyl radical (·OH) is generated via the Fenton-like reaction to cause ferroptosis, and Mn2+ augments cGAS-STING activity to boost immune-driven ferroptosis. In addition, ferroptosis amplifies Mn2+ -induced immunogenic cell death and initiates the antitumor immune "closed loop" along with immune-driven ferroptosis. Notably, this multifunctional nanoplatform is effective in killing both primary and distant tumors.© 2023 Wiley-VCH GmbH.