HSP70-Promoter-Driven CRISPR/Cas9 System Activated by Reactive Oxygen Species for Multifaceted Anticancer Immune Response and Potentiated Immunotherapy

Authors：Zhao, Liang; Li, Dongdong; Zhang, Yuxi; Huang, Qiaoyi; Zhang, Zhenghai; Chen, Chaoran; Xu, Cong-Fei; Chu, Xiao; Zhang, Yu; Yang, Xianzhu^*

Source：ACS Nano, 2022, 16(9): 13821-13833.

DOI：10.1021/acsnano.2c01885

• specific promoter
• CRISPR
• Cas9
• PD-1
• PD-L1 blockade
• immunogenic cell death
• cancer immunotherapy

To address the low response rate to immune checkpoint blockade (ICB) therapy, we propose a specific promoter-driven CRISPR/Cas9 system, F-PC/pHCP, that achieves permanent genomic disruption of PD-L1 and elicits a multifaceted anticancer immune response to potentiate immunotherapy. This system consists of a chlorin e6-encapsulated fluorinated dendrimer and HSP70-promoter-driven CRISPR/Cas9. F-PC/pHCP under 660 nm laser activated the HSP70 promoter and enabled the specific expression of the Cas9 protein to disrupt the PD-L1 gene, preventing immune escape. Moreover, F-PC/pHCP also induced immunogenic cell death (ICD) of tumor cells and reprogrammed the immunosuppressive tumor microenvironment. Overall, this specific promoter-driven CRISPR/Cas9 system showed great anticancer efficacy and, more importantly, stimulated an immune memory response to inhibit distant tumor growth and lung metastasis. This CRISPR/Cas9 system represents an alternative strategy for ICB therapy as well as enhanced cancer immunotherapy.

• Institution
  广东省人民医院