Identification of a novel cuproptosis inducer that induces ER stress and oxidative stress to trigger immunogenic cell death in tumors

Cuproptosis, a copper-dependent form of regulated cell death, has been implicated in the progression and treatment of various tumors. The copper ionophores, such as Disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependence, have been found to induce cuproptosis. However, the limited solubility and effectiveness of the combination of DSF and copper ion restrict its widespread application. In this study, through a random screening of our in-house compound library, we identified a novel cuproptosis inducer, YL21, comprising a naphthoquinone core substituted by two dithiocarbamate groups. The combination of YL21 with copper ion induces cuproptosis by disrupting mitochondrial function and promoting the oligomerization of lipoylated protein DLAT. Further, this combination induces endoplasmic reticulum (ER) stress and oxidative stress, triggering immunogenic cell death (ICD) and subsequently promoting the activation of antitumor immune responses to suppress tumor growth in the mice breast cancer model. Notably, the combination of YL21 and copper ion demonstrated improved solubility and increased antitumor activity compared to the combination of DSF and copper ion. Thus, YL21 functions as a novel cuproptosis inducer and may serve as a promising candidate for antitumor immunotherapy.