Biodegradable ionic nanoregulators for synchronous modulation of copper and iron ion homeostasis in breast cancer therapy

Abnormal copper and iron ion metabolism promotes tumor proliferation but also presents a potential target for cancer therapy. However, simultaneously modulating these two ions is challenging, and the downstream therapeutic mechanisms remain unexplored. Here, we introduce Fe ss TMiR, a biodegradable ionic nanoregulator designed to modulate copper and iron ion homeostasis for tumor treatment. Fe ss TMiR comprises ferrous ions and disulfanediyldiacetic acid-assembled nanovectors (Fe ss NV) combined with tetrathiomolybdate (TM), an anti-copper agent. Under the acidic and high-glutathione conditions of the tumor microenvironment, Fe ss TMiR decomposes into ferrous ions and TM, leading to elevated iron and reduced copper levels. Transcriptome analysis reveals that this dual ion modulation induces cancer cell death via ferroptosis, apoptosis, and autophagy by affecting multiple pathways, including metal ion metabolism, glutathione metabolism, and oxidative stress. Additionally, Fe ss TMiR inhibits angiogenesis and reduces the expression of programmed cell death ligand 1 (PD-L1). Notably, Fe ss TMiR elicits robust antitumor immune responses in breast tumor mouse models, including dendritic cell maturation, Treg cell reduction, and enhanced T cell tumor infiltration. This study underscores the potential of modulating iron and copper homeostasis in tumor therapy, enhancement of antitumor immune responses, and activation of ferroptosis.