癌症免疫疗法
刺
突变体
细胞生物学
癌症研究
免疫疗法
化学
敏化
癌症
生物
生物化学
免疫学
基因
工程类
航空航天工程
遗传学
作者
Lichao Sun,Hongbo Gao,Han Wang,Jingwei Zhang,Xiuru Ji,Yang Jiao,Xiaojia Qin,Dalong Ni,Xiangpeng Zheng
标识
DOI:10.1002/advs.202307278
摘要
Activating cGAS-STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS-STING pathway. Herein, multifunctional ZIF-8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS-STING pathway. The synthesized ZIF-8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS-STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF-8@MnO2 effectively promotes the cGAS-STING pathway and synergizes with PD-L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion-based nanoplatform to enhance the cGAS-STING-mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.
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