Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell(CSC)therapy,while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion,especially hypox...Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell(CSC)therapy,while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion,especially hypoxia-induced CD47 overexpression in CSCs.Herein,we developed a genetically engineered CSC membrane-coated hollow manganese dioxide(hMnO_(2)@gCMs)to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs.The hMnO_(2)core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H_(2)O_(2),thus suppressing the CSCs and reducing the expression of CD47.Cooperating with hypoxia relief-induced downregulation of CD47,the overexpressed SIRPαon gCM shell efficiently blocked the CD47-SIRPα“don’t eat me”pathway,synergistically eliciting robust antitumor-mediated immune responses.In a B16F10-CSC bearing melanoma mouse model,the hMnO_(2)@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth.Our work presents a simple,safe,and robust platform for CSC eradication and cancer immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82222035 and 82372106)the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515110633)+2 种基金the Shenzhen Medical Research Found(No.B2302041)the Shenzhen Science and Technology Program(No.RCBS20221008093123060)the Shenzhen Bay Laboratory Proof-of-Concept Fund(No.S231801005).
文摘Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell(CSC)therapy,while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion,especially hypoxia-induced CD47 overexpression in CSCs.Herein,we developed a genetically engineered CSC membrane-coated hollow manganese dioxide(hMnO_(2)@gCMs)to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs.The hMnO_(2)core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H_(2)O_(2),thus suppressing the CSCs and reducing the expression of CD47.Cooperating with hypoxia relief-induced downregulation of CD47,the overexpressed SIRPαon gCM shell efficiently blocked the CD47-SIRPα“don’t eat me”pathway,synergistically eliciting robust antitumor-mediated immune responses.In a B16F10-CSC bearing melanoma mouse model,the hMnO_(2)@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth.Our work presents a simple,safe,and robust platform for CSC eradication and cancer immunotherapy.
