肿瘤微环境
免疫系统
化学
癌症研究
CD8型
鸟苷
癌细胞
细胞生物学
生物
癌症
生物化学
免疫学
遗传学
作者
Haozhe He,Lili Du,Hongman Xue,Yongcheng An,Kejing Zeng,Huansen Huang,Yulong He,Changhua Zhang,Jun Wu,Xintao Shuai
标识
DOI:10.1002/smtd.202300230
摘要
Abstract 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 Mn 3+ 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 Mn 3+ /Mn 2+ , a hydroxyl radical (·OH) is generated via the Fenton‐like reaction to cause ferroptosis, and Mn 2+ augments cGAS‐STING activity to boost immune‐driven ferroptosis. In addition, ferroptosis amplifies Mn 2+ ‐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.
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