A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy.
10.1016/j.apsb.2022.10.021
- Author:
Qianhua FENG
1
;
Yutong HAO
1
;
Shuaiqi YANG
1
;
Xiaomin YUAN
1
;
Jing CHEN
1
;
Yuying MEI
1
;
Lanlan LIU
2
;
Junbiao CHANG
3
;
Zhenzhong ZHANG
1
;
Lei WANG
1
Author Information
1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
2. Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
3. Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, China.
- Publication Type:Journal Article
- Keywords:
Cerium metal–organic framework;
Drug delivery;
Glutamine metabolism;
Immunogenic tumor cell death;
Immunotherapy;
Lactate oxidase;
Metabolic intervention;
Reactive oxygen species
- From:
Acta Pharmaceutica Sinica B
2023;13(2):775-786
- CountryChina
- Language:English
-
Abstract:
The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.
