Disrupting Copper Homeostasis to Enhance Cuproptosis and Ferroptosis for Glioblastoma Immunotherapy

ABSTRACT Essential metal ions such as copper and iron ions are promising tumor therapeutic targets with the emerging of cuproptosis and ferroptosis. To effectively induce cuproptosis and ferroptosis in tumor cells, copper‐selenium‐naphthazarin nanoparticles (CSN NPs) were rationally fabricated through the modification of ultrasmall Cu 2‐ x Se nanoparticles with naphthazarin. These nanoparticles can disrupt copper homeostasis in glioblastoma (GBM) cells to simultaneously activate cuproptosis/ferroptosis pathways and significantly enhance GBM therapy. Following surgical resection, hydrogel‐mediated sustainable release of CSN NPs within the cavity resulted in the accumulation of copper ions in tumor cells, leading to aggregation of mitochondrial lipoylated proteins and iron‐sulfur cluster protein loss, thereby triggering cuproptosis. Concurrently, CSN NPs triggered ferroptosis through ROS accumulation, GSH depletion, and GPX4 downregulation, due to the joint effects of the Fenton‐like property of Cu 2 ‐ x Se nanoparticles, the Michael reaction between naphthazarin with GSH, and the reduction of Cu 2+ by GSH. The synergistic cuproptosis/ferroptosis induced robust immunogenic cell death (ICD) and remodeled the tumor immuno‐microenvironment through enhanced infiltration of CD8 + and CD4 + T cells. The median survival time of treated GBM mice was increased by 1.9‐fold compared to the untreated GBM‐bearing mice. Our findings demonstrate a promising strategy of coupling cuproptosis‐ferroptosis with immunotherapy through modulation of essential metal ions, presenting an innovative paradigm for GBM postoperative treatment.