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 <i>T</i>₂-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 <i>Col3a1</i> and <i>Col12a1</i> 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.