Osteosarcoma is the most common malignant bone tumor without efficient management for improving 5-year event-free survival.Immunotherapy is also limited due to its highly immunosuppressive tumor microenvironment(TME)....Osteosarcoma is the most common malignant bone tumor without efficient management for improving 5-year event-free survival.Immunotherapy is also limited due to its highly immunosuppressive tumor microenvironment(TME).Pore-forming gasdermins(GSDMs)-mediated pyroptosis has gained increasing concern in reshaping TME,however,the expressions and relationships of GSDMs with osteosarcoma remain unclear.Herein,gasdermin E(GSDME)expression is found to be positively correlated with the prognosis and immune infiltration of osteosarcoma patients,and low GSDME expression was observed.A vector termed as LPAD contains abundant hydroxyl groups for hydrating layer formation was then prepared to deliver the GSDME gene to upregulate protein expression in osteosarcoma for efficient TME reshaping via enhanced pyroptosis induction.Atomistic molecular dynamics simulations analysis proved that the hydroxyl groups increased LPAD hydration abilities by enhancing coulombic interaction.The upregulated GSDME expression together with cleaved caspase-3 provided impressive pyroptosis induction.The pyroptosis further initiated proinflammatory cytokines release,increased immune cell infiltration,activated adaptive immune responses and create a favorable immunogenic hot TME.The study not only confirms the role of GSDME in the immune infiltration and prognosis of osteosarcoma,but also provides a promising strategy for the inhibition of osteosarcoma by pore-forming GSDME gene delivery induced enhanced pyroptosis to reshape the TME of osteosarcoma.展开更多
基金supported in part by National Key Research and Development Program of China(2021YFC2400500)National Natural Science Foundation of China(52273121,52373128)+3 种基金Beijing Natural Science Foundation(7222011)Beijing Hospitals Authority Youth Programme(QML20210402)the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes(BMHC-2021-6,JYY2023-11,JYY2023-8,BJRITO-RDP-2024)Beijing Jishuitan Hospital Program(JSTYC202206,XKXX202114,XKXX202115).The authors also gratefully acknowledge the support of Prof.Fu-Jian Xu and Prof.Bingran Yu from Beijing University of Chemical Technology,China in the preparation of LPAD polymers,and Dr.Jing Li from Jining Medical University,China in the molecule dynamic simulation.
文摘Osteosarcoma is the most common malignant bone tumor without efficient management for improving 5-year event-free survival.Immunotherapy is also limited due to its highly immunosuppressive tumor microenvironment(TME).Pore-forming gasdermins(GSDMs)-mediated pyroptosis has gained increasing concern in reshaping TME,however,the expressions and relationships of GSDMs with osteosarcoma remain unclear.Herein,gasdermin E(GSDME)expression is found to be positively correlated with the prognosis and immune infiltration of osteosarcoma patients,and low GSDME expression was observed.A vector termed as LPAD contains abundant hydroxyl groups for hydrating layer formation was then prepared to deliver the GSDME gene to upregulate protein expression in osteosarcoma for efficient TME reshaping via enhanced pyroptosis induction.Atomistic molecular dynamics simulations analysis proved that the hydroxyl groups increased LPAD hydration abilities by enhancing coulombic interaction.The upregulated GSDME expression together with cleaved caspase-3 provided impressive pyroptosis induction.The pyroptosis further initiated proinflammatory cytokines release,increased immune cell infiltration,activated adaptive immune responses and create a favorable immunogenic hot TME.The study not only confirms the role of GSDME in the immune infiltration and prognosis of osteosarcoma,but also provides a promising strategy for the inhibition of osteosarcoma by pore-forming GSDME gene delivery induced enhanced pyroptosis to reshape the TME of osteosarcoma.
