Cuproptosis represents a novel form of programmed cell death that relies on copper ions and targets the mitochondrial tricarboxylic acid cycle, offering fresh avenues for tumor therapy. Elesclomol, as a highly efficient small-molecule copper ion carrier, transports copper ions into mitochondria. Under the action of ferredoxin-1 (FDX1), it induces abnormal aggregation of lipoylated proteins and loss of iron–sulphur clusters, thereby generating protein toxicity stress and killing tumor cells. Furthermore, elesclomol effectively remodels the tumor immune microenvironment by promoting dendritic cell maturation and CD8+ T cell infiltration, demonstrating synergistic effects with immune checkpoint blockade therapies. However, tumor cells can develop resistance mechanisms through metabolic reprogramming via hypoxia-inducible factor-1α (HIF-1α) and the nuclear factor E2-related factor 2 (Nrf2)-driven reductive pathway, which partially limits the drug’s clinical efficacy. Addressing this limitation, combination therapies integrating elesclomol with targeted agents such as ferroptosis inducers or chemotherapeutic drugs have demonstrated significant antitumor advantages. Future research must urgently leverage the selection of precise biomarkers and the development of novel intelligent nanodelivery systems to further advance the safe and efficient clinical translation of elesclomol.
Peng et al. (Thu,) studied this question.