Amifostine-Iron Nanoparacrystalline for Tumor-Selective Immunogenic Ferroptosis.

Ferroptosis offers potent anticancer potential but suffers from nonselective toxicity and immune suppression. Here, we develop amifostine-iron nanoparacrystalline (AFe-NPC), a self-delivering nanomedicine assembled from a clinically approved cytoprotective prodrug and ferric ions, enabling tumor-selective immunogenic ferroptosis. AFe-NPC with good T2-weighted magnetic resonance imaging (MRI) contrast exhibits superior Fenton catalytic activity and potent glutathione depletion, outperforming commercial Fe3O4 nanoparticles for enabling efficient ferroptosis induction under MRI guidance. Notably, alkaline phosphatase (ALP) with high expression in normal cells can convert amifostine in AFe-NPC into WR-1065, which scavenges reactive oxygen species and upregulates Col3a1 and Col12a1 to enhance ALP activity for strengthening cytoprotection. Conversely, low ALP expression in tumor cells cannot realize effective cytoprotection, causing AFe-NPC to induce immunogenic ferroptosis. AFe-NPC-induced ferroptosis can boost CD8+ T cell-mediated systemic anticancer immunity and synergize with immune checkpoint blockade to eradicate primary and metastatic tumors.