G-quadruplex-guided bifunctional platinum complex induce multiple pyroptosis pathways for antitumor therapy

G-quadruplexes (G4s), as a special nucleic acid secondary structure, is a promising therapeutic target for enhancing immune response. We designed a bifunctional (two Pt-Cl bond) 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 the damage to G4s, facilitating their efflux from the nucleus and thereby activating the 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 instigates 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 the G4s in the context of antitumor immunity, but also open an avenue for the application of G4-guided chemotherapy agents in immunotherapy.