Oxidative Stress and Malignancy: The Central Role of Reactive Oxygen Species (ROS) in Cancer

Abstract

Reactive oxygen species (ROS) are unavoidable byproducts of aerobic metabolism that play a dual and paradoxical role in cancer biology. At physiological levels, ROS function as essential second messengers regulating proliferation, differentiation, and survival signaling. However, excessive ROS accumulation beyond cellular antioxidant capacity induces oxidative stress, leading to DNA damage, genomic instability, and malignant transformation. This review provides a comprehensive synthesis of the molecular mechanisms linking ROS to cancer initiation, progression, and therapeutic vulnerability. We examine the major sources and types of ROS, with particular emphasis on mitochondrial and enzymatic generation, and detail the adaptive antioxidant systems exploited by cancer cells, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPX), total antioxidant capacity (TAC), and lipid peroxidation biomarkers such as malondialdehyde (MDA). The review further elucidates how ROS regulates key oncogenic processes, including DNA mutagenesis, redox-sensitive signaling pathways, epithelial–mesenchymal transition, angiogenesis, and immune evasion. Importantly, we discuss ROS-induced cell death pathways—apoptosis and ferroptosis—and highlight emerging ROS-based therapeutic strategies, including photodynamic therapy, chemodynamic therapy, ferroptosis inducers, and ROS-responsive drug delivery systems. Finally, we explore future directions in personalized ROS-targeted cancer therapy, integrating redox profiling, nanotechnology, and immunotherapy. Collectively, this review underscores ROS not merely as byproducts of cancer metabolism but as central determinants of tumor behavior and promising targets for precision oncology.