Tumor-Generated Reactive Oxygen Species Storm for High-Performance Ferroptosis Therapy

Abstract

Ferroptosis therapy (FT) efficacy of tumors suffers from a relatively low concentration of Fenton agents, limited hydrogen peroxide (H₂O₂) content, and insufficient acidity in the tumor environment (TME), which are unfavorable for reactive oxygen species (ROS) generation based on Fenton or Fenton-like reactions. The glutathione (GSH) overexpression in TME can scavenge ROS and abate the FT performance. In this study, a strategy of ROS storm generation specifically initiated by the TME and our developed nanoplatforms (TAF-HMON-CuP@PPDG) is proposed for high-performance FT of tumors. The GSH in the TME initiates HMON degradation, resulting in tamoxifen (TAF) and copper peroxide (CuP) release from TAF3-HMON-CuP3@PPDG. The released TAF leads to enhanced acidification within tumor cells, which reacts with the released CuP producing Cu²⁺ and H₂O₂. The Fenton-like reaction between Cu²⁺ and H₂O₂ generates ROS and Cu⁺, and that between Cu⁺ and H₂O₂ generates ROS and Cu²⁺, forming a cyclic catalysis effect. Cu²⁺ reacts with GSH to generate Cu⁺ and GSSG. The increased acidification by TAF can accelerate the Fenton-like reaction between Cu⁺ and H₂O₂. The GSH consumption decreases the glutathione peroxidase 4 (GPX4) expression. All of the above reactions generate a ROS storm in tumor cells for high-performance FT, which is demonstrated in cancer cells and tumor-bearing mice.