Dual-Regulated Nanodrug Potentiates Immunotherapy by Synergizing Ferroptosis with Radiotherapy to Reverse the Immunosuppressive Tumor Microenvironment

Immunologically “cold” tumors remain a major challenge in cancer immunotherapy due to their immunosuppressive microenvironment and lack of T-cell infiltration. Inducing immunogenic cell death (ICD) represents a promising strategy to convert cold tumors into immunologically “hot” ones. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has recently emerged as a potent inducer of ICD. However, the efficacy of ferroptosis is often limited by the antioxidant capacity of tumor cells and the lack of targeted immune activation. Herein, we report an iron-based metal-organic framework (MOF) nanoplatform (denoted as Fe-MOF@DS) co-loaded with a disulfiram (DS) derivative for synergistically enhancing ferroptosis and radiotherapy (RT)-mediated immunotherapy in cold tumors. The Fe-MOF core efficiently catalyzes the Fenton reaction, generating reactive oxygen species (ROS) to initiate ferroptosis, while DS inhibits the aldehyde dehydrogenase (ALDH) pathway and depletes glutathione (GSH), further amplifying oxidative stress and lipid peroxidation. When combined with radiotherapy, the system not only enhances ferroptosis but also promotes the release of damage-associated molecular patterns (DAMPs), leading to dendritic cell (DC) maturation and cytotoxic T lymphocyte (CTL) infiltration. In vivo studies using a cold tumor model (4T1 breast carcinoma) demonstrated significant tumor suppression, increased CD8[Formula: see text] T cell infiltration, and abscopal effects, indicating a robust systemic anti-tumor immune response. This work provides a novel nanomedicine strategy for synergizing ferroptosis, radiotherapy, and immunotherapy to treat cold tumors.