Immunosuppressive tumor microenvironment(TME)is a key regulator in the high recurrence and metastasis rate of breast cancer after microwave(MW)thermal therapy.Pyroptosis,a form of programmed cell death initiated by in...Immunosuppressive tumor microenvironment(TME)is a key regulator in the high recurrence and metastasis rate of breast cancer after microwave(MW)thermal therapy.Pyroptosis,a form of programmed cell death initiated by inflammasomes,which can activate tumor immunogenicity and reprogram immune TME.Here,we report an extremely simple Al-based metal-organic frameworks nano-immunoadjuvants(AM NIAs)that programmatically activate nucleotide-binding domain,leucine-rich-containing family,pyrin domain-containing-3(NLRP3)-mediated pyroptosis to enhance MW-immunotherapy(MW-ICB).After entering the TME,AM NIAs programmed activation of NLRP3-mediated pyroptosis by inducing mitochondrial dysfunction,upregulating HSP90 and promoting lysosomal stress.Consequently,substantial amounts of lactate dehydrogenase,interleukin-18(IL-18),and calreticulin are released,which improves immunosuppressive TME and hinders tumor cell proliferation by facilitating T-cell infiltration.The integration of immune checkpoint inhibitors with MW elicits potent immune responses,demonstrating high inhibition of both primary and distant tumors.Thus,a simple yet effective nano-immunoadjuvant is developed to enhance MW-ICB in breast cancer simply by NLRP3-mediated pyroptosis and immunosuppression reversal.展开更多
基金financial support from the Beijing Natural Science Foundation(Nos.4244112,L248042)the National Natural Science Foundation of China(Nos.62405333,62471492,82172048,U21A20378)+4 种基金the China Postdoctoral Science Foundation(No.2023M743599)the Postdoctoral Fellowship Program of CPSF(No.GZC20232772)the Science and Technology Cooperation and Exchange Special Project of Shanxi Province(No.202304041101030)The Science and Education Cultivation Fund of the National Cancer and Regional Medical Center of Shanxi Provincial Cancer Hospital(No.TD2023003)Shanxi Center of Technology Innovation for Controlled and Sustained Release of Nano-drugs(No.202104010911026)。
文摘Immunosuppressive tumor microenvironment(TME)is a key regulator in the high recurrence and metastasis rate of breast cancer after microwave(MW)thermal therapy.Pyroptosis,a form of programmed cell death initiated by inflammasomes,which can activate tumor immunogenicity and reprogram immune TME.Here,we report an extremely simple Al-based metal-organic frameworks nano-immunoadjuvants(AM NIAs)that programmatically activate nucleotide-binding domain,leucine-rich-containing family,pyrin domain-containing-3(NLRP3)-mediated pyroptosis to enhance MW-immunotherapy(MW-ICB).After entering the TME,AM NIAs programmed activation of NLRP3-mediated pyroptosis by inducing mitochondrial dysfunction,upregulating HSP90 and promoting lysosomal stress.Consequently,substantial amounts of lactate dehydrogenase,interleukin-18(IL-18),and calreticulin are released,which improves immunosuppressive TME and hinders tumor cell proliferation by facilitating T-cell infiltration.The integration of immune checkpoint inhibitors with MW elicits potent immune responses,demonstrating high inhibition of both primary and distant tumors.Thus,a simple yet effective nano-immunoadjuvant is developed to enhance MW-ICB in breast cancer simply by NLRP3-mediated pyroptosis and immunosuppression reversal.
