Systems-Level Decoding of Redox Homeostasis in Cancer: From ROS Biology to Therapeutic Vulnerabilities

Reactive oxygen species (ROS) generated during cellular respiration are highly reactive toward proteins, lipids, and DNA. In the context of malignancy, excessive ROS can cause genomic damage, induce mutations, reprogram metabolic pathways, and sustain pro-survival signaling, thereby collectively promoting tumor progression and adaptive fitness. To cope with elevated oxidative stress, tumor cells upregulate antioxidant systems, including the Nrf2-Keap1 axis, the GSH/GPX4 system, and the Trx/TrxR pathway, which collectively maintain ROS within a tolerable range. This redox balance supports malignant growth while simultaneously creating vulnerabilities that may be therapeutically exploited. Current therapeutic strategies can be broadly categorized into two approaches: elevating ROS to levels sufficient to trigger regulated cell death and disrupting redox homeostasis to enhance tumor sensitivity to conventional therapies. However, the spatiotemporal heterogeneity of ROS generation and distribution presents a major challenge to precise therapeutic intervention. Therefore, identifying critical regulatory nodes and establishing robust, quantifiable biomarkers are essential for improving therapeutic precision. Here, we synthesize current knowledge of ROS biology and redox regulation across diverse tumor types, with particular emphasis on therapeutic combinations that integrate redox modulation with metabolic targeting, DNA damage response, and immune activation. Moving forward, quantitative monitoring, systems-level integration, and personalized treatment strategies will be critical for translating redox-based approaches from mechanistic investigation into clinical practice.