22:T4d0,G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4-mediated immune response remains unclear. We designed a novel class of G4-binding organic-platinum hybrids, L¹ -cispt and L¹ -transpt, with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L¹ -transpt-MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding-guided dynamic balance, accompanied by the destruction of the A5-T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue. Furthermore, L¹ -cispt- and L¹ -transpt-mediated genomic dysfunction could activate the retinoic acid-induced gene I (RIG-I) pathway and induce immunogenic cell death (ICD). The use of L¹ -cispt/L¹ -transpt-treated dying cells as therapeutic vaccines stimulated a robust immune response and effectively inhibited tumor growth in vivo. Our findings highlight the importance of the rational combination of specific spatial recognition and covalent locking in G4-trageting drug design and their potential in immunotherapy.23:T40a,The sequence-dependent DNA secondary structures possess structure polymorphism. To date, studies on regulated ligands mainly focus on individual DNA secondary topologies, while lack focus on quadruplex-duplex hybrids (QDHs). Here, we design an organic-metal hybrid ligand L¹ Pt(dien), which matches and selectively binds one type of QDHs with lateral duplex stem-loop (QLDH) with high affinity, while shows poor affinity for other QDHs and individual G4 or duplex DNA. The solution structure of QLDH MYT1L-L¹ Pt(dien) complex was determined by NMR. The structure reveals that L¹ Pt(dien) presents a chair-type conformation, whose large aromatic "chair surface" intercalates into the G-quadruplex-duplex interface via π-π stacking and "backrest" platinum unit interacts with duplex region through hydrogen bonding and electrostatic interactions, showing a highly matched lock-key binding mode. Our work provided guidance for spatial matching design of selectively targeting ligands to QDH structures.24:T53f,G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [e.g., PyPDS (4-(2-aminoethoxy)-N ²,N ⁶-bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins. We found that cisplatin with PyPDS (CP) exhibits stronger specificity for covalent binding to G4 domains even in the presence of large amounts of dsDNA compared with PyPDS either extracellularly or intracellularly. Multiomics analysis reveals that CP can effectively regulate G4 functions, directly damage G4 structures, activate multiple antitumor signaling pathways, including the typical cGAS-STING pathway and AIM2-ASC pathway, trigger a strong immune response and lead to potent antitumor effects. These findings reflect that cisplatin-conjugated specific G4 targeting groups have antitumor mechanisms different from those of classic cisplatin and provide new strategies for the antitumor immunity of metals.

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