Signaling Mechanism of Cuproptosis Activating cGAS-STING Immune Pathway

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 <i>in vivo</i>. 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.