Reactive Oxygen Species in Breast Cancer: From Redox Dysregulation to ROS-Responsive Therapeutics.

Breast cancer is the most frequently diagnosed malignancy among women worldwide, with 2.3 million new cases and approximately 670,000 deaths reported in 2022 alone. Despite advances in therapy, metastasis and acquired drug resistance remain major clinical challenges. Reactive oxygen species (ROS) play a dual role in breast cancer biology: physiological levels sustain normal cellular signaling, moderately elevated levels promote tumorigenesis through DNA damage, proto-oncogene activation, and tumor suppressor inactivation, while excessive accumulation can trigger cancer cell death. This review examines how redox dysregulation contributes to breast cancer initiation and progression through key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2), as well as apoptotic cascades. We evaluate the evidence for dietary and synthetic antioxidants-melatonin, curcumin, vitamins C and E, and carotenoids-as chemopreventive and adjuvant agents, highlighting both their therapeutic promise and the conflicting data on their safety during cancer treatment. We further discuss emerging ROS-responsive nanoagents for targeted drug delivery and immunotherapy, and strategies to exploit redox vulnerabilities in multidrug-resistant breast cancer cells, including induction of ferroptosis, an iron-dependent cell death pathway driven by lipid peroxide accumulation that has emerged as a promising vulnerability in therapy-resistant and mesenchymal-phenotype tumors. Recent advances in machine learning and multi-omics integration, which have begun to identify redox-related gene signatures with prognostic and immunotherapy-predictive value, further point toward precision redox oncology as an emerging clinically actionable framework. By integrating molecular mechanisms with translational advances, this review identifies current gaps and future directions for ROS-targeted therapeutic strategies in breast cancer.