Targeted GPX4 Degradation Mediated by Hypoxia‐Overcoming Nano‐PDTACs for Synergistic Ferroptosis–Immunotherapy

ABSTRACT For triple‐negative breast cancer (TNBC), ferroptosis is a promising therapeutic strategy, with photodynamic therapy (PDT) being an effective method to induce it. However, PDT‐induced ferroptosis has limitations such as poor tumor targeting, unclear target specificity, and hypoxia. Thus, we developed a novel nano‐photodegradation‐targeting chimera (Nano‐PDTAC) that achieves efficient ferroptosis in TNBC cells. The Nano‐PDTAC (PCN@Pt‐TR) is constructed by attaching a GPX4‐targeting peptide (T) and a tumor‐targeting peptide (R) to platinum nanozyme‐modified iron–porphyrin frameworks (PCN@Pt). PCN@Pt‐TR enhances tumor targeting by binding to the αvβ3 integrin receptor on tumor cell surfaces, and it has potential for magnetic resonance imaging (MRI)‐guided therapy. Once inside tumor cells, PCN@Pt‐TR efficiently induces ferroptosis by targeting and degrading the GPX4 protein. Crucially, the O 2 produced by the Pt nanozyme continuously replenished, sustaining the degradation. Additionally, tumor cells undergoing ferroptosis mediated by Nano‐PDTAC can induce immunogenic cell death (ICD), and enhance the effectiveness of immune checkpoint blockade. Thus, this is a valuable approach for inducing ferroptosis based on GPX4‐targeted Nano‐PDTAC, which can overcome the many issues associated with traditional photosensitizers in ferroptosis and may advance the application of ferroptosis in tumor immunotherapy.