In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect.
10.1016/j.apsb.2024.08.028
- Author:
Shujun LIU
1
;
Shijun YUAN
1
;
Meichen LIU
1
;
Jinhu LIU
1
;
Shunli FU
1
;
Tong GAO
1
;
Shuang LIANG
1
;
Xinyan HUANG
1
;
Xinke ZHANG
2
;
Yongjun LIU
1
;
Zipeng ZHANG
3
;
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.
2. Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
3. Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250062, China.
- Publication Type:Journal Article
- Keywords:
CAR-T therapy;
CD55;
ICOSL+ B cell;
Immunogenic cell death;
Immunotherapy;
MHC-I;
T cell recognition;
Tumor engineering
- From:
Acta Pharmaceutica Sinica B
2025;15(1):627-641
- CountryChina
- Language:English
-
Abstract:
The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL+ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual-conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL+ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.
