Signaling Mechanism\nof Cuproptosis Activating cGAS-STING\nImmune Pathway

Copper-mediated programmed cell death, which influences\nthe regulation\nof tumor progression, is an effective approach for antitumor molecular\ntherapy. Unlike apoptosis, copper complex-induced cuproptosis by lipid-acylated\nprotein aggregation triggers the mitochondrial proteotoxic stress\nresponse, which could be associated with immunomodulation. However,\nit remains a great challenge to understand the distinctive molecular\nmechanisms that presumably activate immunity by cuproptosis. Here,\nthe new nonlabeling fluorescent molecular tools of Cu-DPPZ-Py<sup>+</sup> and Cu-DPPZ-Ph are synthesized and used to investigate the\ndifferential immune signaling mechanisms induced by copper-mediated\ncuproptosis or apoptosis. With Cu-DPPZ-Py<sup>+</sup> and Cu-Elesclomol,\nthere is strong evidence that the triggering cuproptosis significantly\ndrives mitochondrial DNA (mtDNA) release to activate innate immunity\nvia cyclic GMP-AMP synthase-stimulation of interferon genes (cGAS-STING),\nwhich can improve T cell antitumor immunity <i>in vivo</i>. By contrast, it is observed that Cu-DPPZ-Ph treated tumor cells\ncould release intracellular caspase-3, resulting in apoptosis-associated\nimmunosuppression. This study supports insights into how cuproptosis\nbridges cGAS-STING immune pathways, contributing to the development\nof cuproptosis-based antitumor immunotherapy.