先天免疫系统
肿瘤微环境
干扰素基因刺激剂
干扰素
化学
免疫系统
免疫疗法
癌症研究
癌症免疫疗法
免疫
免疫学
生物
作者
Lin Hou,Chunyu Tian,Yingshan Yan,Lewen Zhang,Huijuan Zhang,Zhenzhong Zhang
出处
期刊:ACS Nano
[American Chemical Society]
日期:2020-04-16
卷期号:14 (4): 3927-3940
被引量:231
标识
DOI:10.1021/acsnano.9b06111
摘要
Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are essential components of the innate immune sensors to cytosolic DNA and elicit type I interferon (IFN). Recent studies have revealed that manganese (Mn) can enhance cGAS and STING activation to viral infection. However, the role of Mn in antitumor immunity has not been explored. Here, we designed a nanoactivator, which can induce the presence of DNA in cytoplasm and simultaneously elevate Mn2+ accumulation within tumor cells. In detail, amorphous porous manganese phosphate (APMP) NPs that are highly responsive to tumor microenvironment were employed to construct doxorubicin (DOX)-loaded and phospholipid (PL)-coated hybrid nanoparticles (PL/APMP-DOX NPs). PL/APMP-DOX NPs were stably maintained during systemic circulation, but triggered to release DOX for inducing DNA damage and Mn2+ to augment cGAS/STING activity. We found that PL/APMP-DOX NPs with superior tumor-targeting capacity boosted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. Furthermore, the NPs increased production of type I IFN and secretion of pro-inflammatory cytokines (for example, TNF-α and IL-6). Consequently, PL/APMP-DOX NPs exhibited excellent antitumor efficacy and prolonged the lifespan of the tumor-bearing mice. Collectively, we developed a PL-decorated Mn-based hybrid nanoactivator to intensify immune activation and that might provide therapeutic potential for caner immunotherapy.
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