Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade |
| |
Authors: | Zhian Chen Zhenhao Li Huilin Huang Guodong Shen Yingxin Ren Xinyuan Mao Lingzhi Wang Zhenyuan Li Weisheng Wang Guoxin Li Bingxia Zhao Weihong Guo Yanfeng Hu |
| |
Affiliation: | 1. Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515 P. R. China;2. Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 P. R. China |
| |
Abstract: | Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses. |
| |
Keywords: | cancer immunotherapy cGAS-STING signaling efferocytosis homotypic targeting innate immunity |
|
|