Advances in Fenton Reaction-Mediated Ferroptosis for Enhanced Cancer Therapy: Mechanisms, Amplification Strategies, and Synergistic Approaches

Abstract

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising strategy for cancer therapy. The core of this process is the Fenton reaction, in which ferrous ions (Fe²⁺) catalyzes hydrogen peroxide (H₂O₂) into hydroxyl radicals (•OH), triggering a cascade of oxidative damage that selectively destroys tumor cells with dysregulated iron metabolism and redox imbalance. Recent advances have transformed Fenton chemistry from a classical redox reaction into a precision therapeutic engine for amplifying ferroptosis in situ. This review summarizes the molecular mechanisms of ferroptosis and highlight advanced strategies to enhance Fenton-driven lipid peroxidation through nanocatalyst engineering, tumor microenvironment modulation, and self-supplying H₂O₂ systems. Furthermore, we discuss synergistic therapies integrating ferroptosis with chemotherapy, radiotherapy, photothermal and photodynamic therapy, gas therapy, and immunotherapy, to overcome resistance and promote immunogenic cell death. Emerging designs exploit tumor-specific features such as acidic pH, high peroxide flux, and aberrant iron metabolism to achieve spatially confined oxidative lethality with minimal systemic toxicity. Collectively, Fenton reaction-mediated ferroptosis represents a transformative strategy that converts the intrinsic redox fragility of tumors into a therapeutic advantage, offering new directions for next-generation cancer treatment.