CELL INTELLIGENCE · 肿瘤细胞治疗研究

OBJECTIVE: Gastric cancer (GC) is a prevalent malignant tumor that warrants the development of drugs and therapeutic targets. Cuproptosis has emerged as a promising mechanism by which to inhibit tumors because copper homeostasis disorders frequently occur in various malignancies. The combination of disulfiram (DSF) and copper ions (DSF/Cu) has been shown to have significant antitumor effects. This study utilized DSF/Cu to investigate the mechanism underlying cuproptosis in GC cells. METHODS: GC cells were treated with DSF/Cu and protein sequencing was performed to screen for differentially expressed genes. The mechanism by which overexpressed FDX1 regulates cuproptosis and WDR43 expression was determined. Subsequently, how to improve the efficacy of DSF/Cu in the treatment of GC was studied in a mouse model of GC. RESULTS: DSF/Cu had a good therapeutic effect on promoting cuproptosis in GC cells. Protein sequencing revealed WDR43 as a downstream gene of FDX1 . Increasing the expression of FDX1 enhanced the sensitivity of GC cells to copper treatment and inhibited the expression of WDR43 , thereby exerting an antitumor effect. Furthermore, DSF/Cu was loaded into exosomes derived from natural killer (NK) cells to enhance the biological safety and tumor targeting of DSF/Cu and validate the inhibitory effect on GC both in vitro and in vivo . CONCLUSIONS: This study showed that DSF/Cu promoted cuproptosis and the expression of FDX1 affected cuproptosis sensitivity of GC. Moreover, the combination of NK cell exosomes with DSF/Cu improved the therapeutic effect of DSF/Cu, which helps to promote the targeted therapy of GC and improve clinical applicability.