On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition.
10.1016/j.apsb.2022.09.004
- Author:
Xiaoqing LIU
1
;
Shuang LIANG
1
;
Xiao SANG
1
;
Lili CHANG
1
;
Shunli FU
1
;
Han YANG
1
;
Huizhen YANG
1
;
Yongjun LIU
1
;
Na ZHANG
1
Author Information
1. Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
- Publication Type:Journal Article
- Keywords:
Augmented immunogenic cell death;
BRD4 inhibition;
Cold tumors;
Differ-targeting delivery;
Dual immune checkpoint inhibition;
Increased DNA damage;
MMP-2 sensitive;
Nano-engager
- From:
Acta Pharmaceutica Sinica B
2023;13(4):1740-1754
- CountryChina
- Language:English
-
Abstract:
Cancer immunotherapy has become a promising strategy. However, the effectiveness of immunotherapy is restricted in "cold tumors" characterized with insufficient T cells intratumoral infiltration and failed T cells priming. Herein, an on-demand integrated nano-engager (JOT-Lip) was developed to convert cold tumors to hot via "increased DNA damage and dual immune checkpoint inhibition" strategy. JOT-Lip was engineered by co-loading oxaliplatin (Oxa) and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies (Tim-3 mAb) coupled on the liposomal surface by metalloproteinase-2 (MMP-2)-sensitive linker. JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death (ICD) of Oxa, thus promoting T cells intratumoral infiltration. In addition, JQ1 inhibited PD-1/PD-L1 pathway, achieving dual immune checkpoint inhibition combining with Tim-3 mAb, thus effectively promoting T cells priming. It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns (DAMPs), but also enhanced T cells intratumoral infiltration and promoted T cell priming, which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects. Collectively, our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot, which holds great potential in clinical cancer chemoimmunotherapy.
