G-quadruplexes(G4s),as special nucleic acid secondary structures,are promising therapeutic targets for enhancing immune response.We designed a bifunctional(two Pt-Cl bonds)PyPDSplatin complex(BiPP)by coupling PyPDS wi...G-quadruplexes(G4s),as special nucleic acid secondary structures,are promising therapeutic targets for enhancing immune response.We designed a bifunctional(two Pt-Cl bonds)PyPDSplatin complex(BiPP)by coupling PyPDS with cisplatin.Due to the retention of two chlorine atoms,BiPP can covalently bind to two sites on G4s,thereby enhancing binding stability.BiPP retains the classical cisplatin structure,which helps to maintain it in a neutral or weakly charged state,facilitating the passage of dichloroplatin complexes across the cell membrane.BiPP not only significantly bolstered the antitumor efficacy of chemotherapy but also induced damage to G4s,facilitating their efflux from the nucleus and thereby activating a synergistic interplay between the absent in melanoma 2-apoptosis-associated speck-like protein containing a CARD(AIM2-ASC)and cyclic GMP-AMP synthase-stimulator of the interferon gene(cGAS-STING)pathways.Moreover,BiPP initiated a molecular cascade that triggers pyroptosis by down-regulating baculoviral IAP repeat containing 7(BIRC7)gene expression.During this process,caspase-3 is activated to cleave gasdermin E(GSDME),releasing its N-terminal domain(GSDNE-N),which subsequently induces pyroptosis.This interaction culminates in the formation of a highly integrated antitumor immune network in conjunction with the BIRC7-caspase-3-GSDME system.Our findings not only unveil the pivotal role played by G4s in the context of antitumor immunity,but also open an avenue for the application of G4-guided chemotherapy agents in immunotherapy.展开更多
基金support from the National Key Research and Development Program of China[2022YFB3804502]the National Natural Science Foundation of China[92353301,22277151,22293053,22007103,22293050,and 22307054]+4 种基金the Natural Science Foundation of Guangdong Province[2024B1515020083]the Guangzhou Science and Technology Plan Project[2023A04J1941]the Fundamental Research Funds for the Central Universities,the China National Postdoctoral Program for Innovative Talents(BX20230154)the China Postdoctoral Science Foundation(2023M731591)the Jiangsu Funding Program for Excellent Postdoctoral Talent(2023ZB201).
文摘G-quadruplexes(G4s),as special nucleic acid secondary structures,are promising therapeutic targets for enhancing immune response.We designed a bifunctional(two Pt-Cl bonds)PyPDSplatin complex(BiPP)by coupling PyPDS with cisplatin.Due to the retention of two chlorine atoms,BiPP can covalently bind to two sites on G4s,thereby enhancing binding stability.BiPP retains the classical cisplatin structure,which helps to maintain it in a neutral or weakly charged state,facilitating the passage of dichloroplatin complexes across the cell membrane.BiPP not only significantly bolstered the antitumor efficacy of chemotherapy but also induced damage to G4s,facilitating their efflux from the nucleus and thereby activating a synergistic interplay between the absent in melanoma 2-apoptosis-associated speck-like protein containing a CARD(AIM2-ASC)and cyclic GMP-AMP synthase-stimulator of the interferon gene(cGAS-STING)pathways.Moreover,BiPP initiated a molecular cascade that triggers pyroptosis by down-regulating baculoviral IAP repeat containing 7(BIRC7)gene expression.During this process,caspase-3 is activated to cleave gasdermin E(GSDME),releasing its N-terminal domain(GSDNE-N),which subsequently induces pyroptosis.This interaction culminates in the formation of a highly integrated antitumor immune network in conjunction with the BIRC7-caspase-3-GSDME system.Our findings not only unveil the pivotal role played by G4s in the context of antitumor immunity,but also open an avenue for the application of G4-guided chemotherapy agents in immunotherapy.
