Advances in Fenton reaction-mediated ferroptosis for enhanced cancer therapy: mechanisms, amplification strategies, and synergistic approaches.

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+) catalyze hydrogen peroxide (H2O2) into hydroxyl radicals (˙OH), triggering oxidative damage that preferentially destroys tumor cells with iron metabolism and redox dysregulation. 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 highlights 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 is a transformative strategy that converts the intrinsic redox fragility of tumors into a therapeutic advantage, offering new directions for next-generation cancer treatment.