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Being a recently identified mode of programmed cell demise, the functional implications of cuproptosis in the genesis, progression, and therapeutic modulation of cancer remain largely unknown. Given that cuproptosis is predominantly elicited by cellular copper overload, notably attributable to the dysregulation of copper homeostasis within mitochondria, we designed a series of phosphorescent rhenium(I) complexes ( Re1 – Re5 ) as suborganelle-targeted copper ionophores. Among them, Re5 can successfully transport extracellular copper into mitochondria and the Golgi apparatus and especially enrich copper into mitochondria. Consequently, Re5 breaks the cellular redox balance and disturbs the energetic and metabolism pathways to induce cuproptosis. Finally, we prove that Re5 can promote immune responses and modulate cancer immune microenvironments. In all, we present here the first subcellular organelle-targeted copper ionophore and prove that cuproptosis-inducing small molecules are potent cancer immunotherapeutic candidates.
Ling et al. (Mon,) studied this question.