Evoking Simultaneous Ferroptosis and Apoptosis by a Dual‐Locked Platinum (IV) Prodrug for Synergistic Chemo‐immunotherapy

Abstract

Abstract While platinum‐based chemotherapeutics have revolutionized cancer treatment, their clinical potential is limited by off‐target toxicity and restricted antitumor mechanisms. Herein, we introduce a dual‐locked Pt(IV) prodrug designed for tumor‐specific activation, combining platinum‐based chemotherapy with TLR7/8‐mediated immunotherapy. The prodrug features a γ‐glutamyl‐caged TLR7/8 agonist as an axial ligand, enabling sequential activation by elevated glutathione (GSH) and γ‐glutamyltranspeptidase (GGT) in the tumor microenvironment. Reduction of the Pt(IV) core releases cisplatin and depletes intracellular reductants, amplifying reactive oxygen species to trigger synergistic ferroptosis and apoptosis. Concurrently, GGT‐cleaved axial ligand activates tumor‐associated macrophages and dendritic cells, repolarizing immunosuppressive M2‐like macrophages to pro‐inflammatory M1‐like phenotypes while recruiting effector and memory T cells. In murine models, the Pt(IV) prodrug demonstrated potent antitumor efficacy by confining immune activation to malignant tissues, eradicating primary tumors, and establishing durable protective immunity against recurrence. This spatiotemporally controlled dual‐release strategy minimizes systemic toxicity while synergizing chemotherapy and immunotherapy, offering a transformative approach for targeted cancer therapy.