刺
癌症研究
免疫系统
肿瘤微环境
兴奋剂
封锁
医学
免疫增强剂
肿瘤进展
免疫检查点
CD8型
细胞毒性T细胞
免疫疗法
药理学
免疫学
癌症
化学
内科学
受体
体外
航空航天工程
工程类
生物化学
作者
Huanling Guo,Jinsheng Huang,Tan Yang,Wenxin Wu,Tongyi Huang,Nan Zhang,Shuling Chen,Chunyang Zhang,Xiaoyan Xie,Xintao Shuai,Ming Xu
出处
期刊:Nano Today
[Elsevier]
日期:2022-02-18
卷期号:43: 101425-101425
被引量:21
标识
DOI:10.1016/j.nantod.2022.101425
摘要
The PD-1/PD-L1 blockade failed to prolong the progression-free survival of patients after radiofrequency ablation (RFA) treatment of liver metastases from colorectal cancers. We found that the PD-1/PD-L1 immune checkpoint blockade (ICB) therapy after RFA in mice model only had a temporary inhibition of tumor progression due to the limited number of mature dendritic cells (DCs) and the insufficient tumor infiltration/activation of cytotoxic T lymphocytes (CTLs). Our study further revealed that the activation of stimulator of interferon gene (STING) affecting tumor-infiltrating DCs and CD8+ T cells was only transient after RFA of tumor. Therefore, a nanovesicle capable of releasing the anti-PD-L1 antibody (αPD-L1) and STING agonist inside tumor in a spatiotemporally controlled manner was developed to evoke a robust anti-cancer immune response and immune memory for a long-term inhibition of tumor progression after RFA. The nanovesicle entrapping the hydrophilic STING agonist 5,6-dimethylxanthenone-4-acetate sodium salt (DMXAAst) in its lumen and anchoring αPD-L1 via an MMP-2-sensitive peptide linker was coated with PEG layer sheddable in acidic tumor microenvironment. The nanodrug design allowed the PEG coating to block off-target interaction between αPD-L1 and PD-L1-positive normal cells in blood and normal tissues, thereby reducing the immune-related adverse effects (irAEs). APD-L1 was firstly released in response to MMP-2 overexpressed in tumor tissue for ICB therapy, which promote the intracellular delivery of DMXAAst to activate STING in DCs. The synergistic effect of αPD-L1, DMXAAst and RFA evoked a robust anti-tumor immunity and long-term immune memory for a potent cancer therapy.
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