Affiliation:
1. Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China
2. Department of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia
3. Department of Gynecologic Oncology Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital Chongqing 400030 China
4. School of Basic Medicine Health Science Center Yangtze University Jingzhou 434000 China
Abstract
AbstractChemo‐immunotherapy has shown great success in boosting systemic anti‐tumor effects in the clinic. However, cancer cells can escape the maximum impact of chemotherapy through intracellular symbiotic bacteria and abnormally activated macropinocytosis, while cancer immune evasion is largely facilitated by the programmed cell death 1 ligand 1 (PD‐L1) protein and tumor‐secreted exosomes. To efficiently sensitize chemo‐immunotherapy, the clinical mitoxantrone (MTO) is therefore rationally coordinated with Cu2+ to develop nanoscale metal‐organic frameworks (MTO‐Cu), then loaded with the macropinocytosis and exosome secretion inhibitor amiloride (AMI) and modified with targeted chondroitin sulfate (CS) to form CS/MTO‐Cu@AMI nanoadjuvant. Notably, the coordinated Cu2+ effectively triggers cuproptosis‐induced mitochondrial dysfunction, which activates AMPK pathway‐mediated PD‐L1 protein degradation, deprives energy supply for macropinocytosis and exosome release, and amplifies oxidative stress for deactivating intracellular bacteria, thus efficiently sensitizing chemo‐immunotherapy. Meanwhile, AMI suppresses macropinocytosis and exosome secretion to act synergistically with Cu2+‐caused chemo‐immunotherapy potentiation. Moreover, damaged dsDNA during CS/MTO‐Cu@AMI treatment activates the cGAS‐STING pathway, further evoking the anti‐tumor immunity. Additionally, the attached CS endows CS/MTO‐Cu@AMI with specific tumor targeting and hyaluronidase‐responsive charge reversal property, while MTO‐Cu endows this nanoadjuvant with pH/GSH dual‐responsive release behavior. Therefore, CS/MTO‐Cu@AMI efficiently sensitizes chemotherapy and activates systemic antitumor immunity in vitro and in vivo, providing an innovative solution to potentiate cancer chemo‐immunotherapy.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
West China Hospital, Sichuan University
Subject
Electrochemistry,Condensed Matter Physics,Biomaterials,Electronic, Optical and Magnetic Materials
Cited by
22 articles.
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