The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma(GBM)patients.The obs...The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma(GBM)patients.The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein,facilitating tumor immune evasion.This study presents a pH-adapted excited state intramolecular proton transfer(ESIPT)-isomerizedβ-ketoamide-based covalent organic framework(COF)nanoplatform(denoted as OT@COF-RVG).Temozolomide(TMZ)and OSMI-4(O-GlcNAc transferase inhibitor)were integrated into COF cavities,then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29,showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy(PDT).By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1,OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade(ICB)therapy.Additionally,treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species(ROS)levels,thereby re-establishing an immunostimulatory state,inducing immunogenic cell death(ICD).In summary,our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors,while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.展开更多
基金supported by grants from the Natural Science Foundation of Jiangxi Province(No.20232BAB206085 and 20224BAB216074 for TFY,No.20232BAB216084 for LY)Postdoctoral Research Foundation of China(No.2022M721452 for TFY)。
文摘The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma(GBM)patients.The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein,facilitating tumor immune evasion.This study presents a pH-adapted excited state intramolecular proton transfer(ESIPT)-isomerizedβ-ketoamide-based covalent organic framework(COF)nanoplatform(denoted as OT@COF-RVG).Temozolomide(TMZ)and OSMI-4(O-GlcNAc transferase inhibitor)were integrated into COF cavities,then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29,showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy(PDT).By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1,OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade(ICB)therapy.Additionally,treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species(ROS)levels,thereby re-establishing an immunostimulatory state,inducing immunogenic cell death(ICD).In summary,our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors,while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.
