Redox-modulation of regulated cell death: implications for synergistic anticancer therapies

Reactive oxygen and nitrogen species (RONS) constitute a unifying molecular axis across various cancer therapy modalities and are primary regulators of regulated cell death (RCD). Generally, cancer cells function under high oxidative stress to maintain proliferation, making them vulnerable to therapeutic approaches that push RONS levels above their survival threshold. The purpose of this review is to consolidate mechanistic evidence linking redox modulation to therapeutic efficacy. We analyzed current literature regarding standard and emerging anticancer modalities, including radiotherapy, proton therapy, FLASH therapy, chemotherapy, cold atmospheric plasma, photodynamic therapy, and engineered nanoplatforms. We specifically examined the molecular mechanisms by which these therapies induce mitochondrial ROS accumulation and trigger distinct cell death pathways. Our literature review indicates that these diverse modalities achieve tumor selectivity by increasing mitochondrial ROS beyond cytotoxic limits. When combined strategically, they further promote tumor-specific oxidative stress, maximizing therapeutic efficacy while minimizing damage to healthy tissues. We also highlight the critical biosafety considerations and regulatory frameworks necessary for the safe clinical translation of these RONS-based treatments. Redox-modulating strategies can address critical challenges, including chemoradiation resistance, metabolic rewiring, and the persistence of cancer stem cells. We propose that RONS-centered therapeutic design represents a viable strategy to improve the efficacy of contemporary cancer treatments by combining redox biology with cutting-edge therapeutic engineering. This graphical abstract depicts how various cancer treatment modalities cause RONS-mediated oxidative stress, hence activating different cell death pathways in cancer cells.