Ultrasmall Metal TPZ Complexes with Deep Tumor Penetration for Enhancing Radiofrequency Ablation Therapy and Inducing Antitumor Immune Responses

Abstract Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small satellite lesions after insufficient RFA (iRFA) are difficult to remove, often leading to metastasis and recurrence. Here, Fe‐TPZ nanoparticles are designed by metal ion and (TPZ) ligand complexation for synergistic enhancement of RFA residual tumor therapy. Fe‐TPZ nanoparticles are cleaved in the acidic microenvironment of the tumor to generate Fe 2+ and TPZ. TPZ, an anoxia‐dependent drug, is activated in residual tumors and generates free radicals to cause tumor cell death. Elevated Fe 2+ undergoes a redox reaction with glutathione (GSH), inducing a strong Fenton effect and promoting the production of the highly toxic hydroxyl radical (•OH). In addition, the ROS/GSH imbalance induced by this treatment promotes immunogenic cell death (ICD), which triggers the release of damage‐associated molecular patterns, macrophage polarization, and lymphocyte infiltration, thus triggering a systemic antitumor immune response and noteworthy prevention of tumor metastasis. Overall, this integrated treatment program driven by multiple microenvironment‐dependent pathways overcomes the limitations of the RFA monotherapy approach and thus improves tumor prognosis. Furthermore, these findings aim to provide new research ideas for regulating the tumor immune microenvironment.