Balanced Duality: H₂O₂-Based Therapy in Cancer and Its Protective Effects on Non-Malignant Tissues

Conventional cancer therapy strategies, although centered around killing tumor cells, often lead to severe side effects on surrounding normal tissues, thus compromising the chronic quality of life in cancer survivors. Hydrogen peroxide (H₂O₂) is a secondary signaling molecule that has an array of functions in both tumor and normal cells, including the promotion of cell survival pathways and immune cell modulation in the tumor microenvironment. H₂O₂ is a reactive oxygen species (ROS) crucial in cellular homeostasis and signaling (at concentrations maintained under nM levels), with increased steady-state levels in tumors relative to their normal tissue counterparts. Increased steady-state levels of H₂O₂ in tumor cells, make them vulnerable to oxidative stress and ultimately, cell death. Recently, H₂O₂-producing therapies-namely, pharmacological ascorbate and superoxide dismutase mimetics-have emerged as compelling complementary treatment strategies in cancer. Both pharmacological ascorbate and superoxide dismutase mimetics can generate excess H₂O₂ to overwhelm the impaired H₂O₂ removal capacity of cancer cells. This review presents an overview of H₂O₂ metabolism in the physiological and malignant states, in addition to discussing the anti-tumor and normal tissue-sparing mechanism(s) of, and clinical evidence for, two H₂O₂-based therapies, pharmacological ascorbate and superoxide dismutase mimetics.