Signaling Mechanism of Cuproptosis Activating cGAS-STING Immune Pathway

• Published in: JACS Au 2024-10, Vol.4 (10), p.3988-3999
• Main Authors: Zhu, Chengyuan, Li, Jialiang, Sun, Wanying, Li, Desheng, Wang, Yiliang, Shen, Xing-Can
• Format: Article
• Language: English
• ISSN: 2691-3704; 2691-3704
• DOI: 10.1021/jacsau.4c00712

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 in vivo. 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.