Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2–Keap1 axis to adapt to these conditions, leading to redox plasticity and “Nrf2 addiction” in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc–, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.
Uddin et al. (Thu,) studied this question.