Tumor-Generated Reactive Oxygen Species Storm for High-Performance Ferroptosis Therapy
Lin Huang, Jiaoyang Zhu, Wei Xiong, Jie Feng, Jing Yang, Xuanyi Lu, Yudie Lu, Qianqian Zhang, Peiwei Yi, Yanqiu Feng, Shuai Guo, Xiaozhong Qiu, Yikai Xu, Zheyu Shen
Abstract
Ferroptosis therapy (FT) efficacy of tumors suffers from a relatively low concentration of Fenton agents, limited hydrogen peroxide (H 2 O 2 ) 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 Cu 2+ and H 2 O 2 . The Fenton-like reaction between Cu 2+ and H 2 O 2 generates ROS and Cu +, and that between Cu + and H 2 O 2 generates ROS and Cu 2+, forming a cyclic catalysis effect. Cu 2+ reacts with GSH to generate Cu + and GSSG. The increased acidification by TAF can accelerate the Fenton-like reaction between Cu + and H 2 O 2 . 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.