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

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.