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)-N²,N⁶-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.

中文翻译：

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G-四链体引导的顺铂触发靶向化疗和免疫治疗的多种途径


G-四链体（G4）是参与人类基本生物过程的非典型核酸结构，并受小分子调节。迄今为止，吡啶他汀及其衍生物[例如，PyPDS (4-(2-氨基乙氧基)-N ² ,N ⁶ -bis(4-(2-(pyrrolidin-1- yl)乙氧基)喹啉-2-基)吡啶-2,6-二甲酰胺)]是应用最广泛的G4结合小分子，被认为具有最好的G4特异性，这为顺铂结合的开发提供了新的选择脱氧核糖核酸。通过将 PyPDS 与顺铂及其类似物结合，我们合成了三种铂配合物，命名为 PyPDSplatins。我们发现，与细胞外或细胞内的 PyPDS 相比，即使在存在大量 dsDNA 的情况下，顺铂与 PyPDS (CP) 也表现出更强的与 G4 结构域共价结合的特异性。多组学分析表明，CP可以有效调节G4功能，直接破坏G4结构，激活多种抗肿瘤信号通路，包括典型的cGAS-STING通路和AIM2-ASC通路，引发强烈的免疫反应，产生有效的抗肿瘤作用。这些发现反映了顺铂缀合的特异性G4靶向基团具有不同于经典顺铂的抗肿瘤机制，并为金属的抗肿瘤免疫提供了新的策略。