Zhu Chengyuan, Li Jialiang, Sun Wanying, Li Desheng, Wang Yiliang, Shen Xing-Can
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
JACS Au. 2024 Sep 20;4(10):3988-3999. doi: 10.1021/jacsau.4c00712. eCollection 2024 Oct 28.
Copper-mediated programmed cell death, which influences the regulation of tumor progression, is an effective approach for antitumor molecular therapy. Unlike apoptosis, copper complex-induced cuproptosis by lipid-acylated protein aggregation triggers the mitochondrial proteotoxic stress response, which could be associated with immunomodulation. However, it remains a great challenge to understand the distinctive molecular mechanisms that presumably activate immunity by cuproptosis. Here, the new nonlabeling fluorescent molecular tools of Cu-DPPZ-Py and Cu-DPPZ-Ph are synthesized and used to investigate the differential immune signaling mechanisms induced by copper-mediated cuproptosis or apoptosis. With Cu-DPPZ-Py and Cu-Elesclomol, there is strong evidence that the triggering cuproptosis significantly drives mitochondrial DNA (mtDNA) release to activate innate immunity via cyclic GMP-AMP synthase-stimulation of interferon genes (cGAS-STING), which can improve T cell antitumor immunity . By contrast, it is observed that Cu-DPPZ-Ph treated tumor cells could release intracellular caspase-3, resulting in apoptosis-associated immunosuppression. This study supports insights into how cuproptosis bridges cGAS-STING immune pathways, contributing to the development of cuproptosis-based antitumor immunotherapy.
铜介导的程序性细胞死亡影响肿瘤进展的调控，是抗肿瘤分子治疗的一种有效方法。与细胞凋亡不同，铜复合物通过脂酰化蛋白聚集诱导的铜死亡触发线粒体蛋白毒性应激反应，这可能与免疫调节有关。然而，了解可能通过铜死亡激活免疫的独特分子机制仍然是一个巨大的挑战。在此，合成了新型非标记荧光分子工具Cu-DPPZ-Py和Cu-DPPZ-Ph，并用于研究铜介导的铜死亡或细胞凋亡诱导的差异免疫信号机制。使用Cu-DPPZ-Py和铜硫辛酸，有强有力的证据表明，触发铜死亡通过环磷酸鸟苷-腺苷酸合酶-干扰素基因刺激物（cGAS-STING）显著驱动线粒体DNA（mtDNA）释放以激活先天免疫，这可以改善T细胞抗肿瘤免疫。相比之下，观察到Cu-DPPZ-Ph处理的肿瘤细胞可释放细胞内半胱天冬酶-3，导致与细胞凋亡相关的免疫抑制。这项研究支持了对铜死亡如何连接cGAS-STING免疫途径的见解，有助于基于铜死亡的抗肿瘤免疫疗法的发展。
