The Biphasic Role of Reactive Oxygen Species in Ovarian Cancer Progression and Therapeutics: Crosstalk Among Metabolism, Ferroptosis, and the Tumor Immune Microenvironment.

Authors

Yixin Hou, Yue Jiang, Hui Li, Meng Jiang, Yanhua Han, Yuehui Zhang

Published in

Critical reviews in oncology/hematology. Pages 105542. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system, and its frequent recurrence and treatment resistance are major obstacles to improving patient outcomes. Studies indicate that the progression and treatment resistance of OC are driven by substantial metabolic and mitochondrial reprogramming. As key byproducts and signaling molecules of mitochondrial metabolism, reactive oxygen species (ROS) have emerged as a central regulatory node in both OC progression and treatment response. While tumor cells enhance their redox-buffering capacity to maintain survival, a trait that exhibits high heterogeneity across histologic subtypes, ROS ultimately exert a biphasic effect determined by dose, spatiotemporal dynamics, and cellular state. On the one hand, a chronic low-to-moderate oxidative burden sustains redox-sensitive prosurvival signaling and drives tumor proliferation, angiogenesis, and invasion. This is primarily achieved by activating antioxidant pathways, such as the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which mediates resistance to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. On the other hand, an acute surge in oxidative stress that breaches the cellular antioxidant-buffering threshold triggers regulated cell death, primarily through the intrinsic mitochondrial apoptotic pathway and iron-dependent lipid peroxidation (ferroptosis). Crucially, ROS-induced ferroptosis and metabolic shifts do not occur in isolation; they actively participate in extensive crosstalk with the tumor immune microenvironment (TIME). Given this complex biology, targeting redox balance represents a highly promising therapeutic strategy. Interventions include scavenging ROS to block prosurvival signaling, or employing specific drugs and nanodelivery systems to amplify oxidative stress to lethal levels. When rationally combined with immunotherapies, these ROS-modulating strategies can effectively reverse tumor resistance by remodeling the TIME. This review systematically summarizes the biological properties of ROS, the mechanisms of metabolic and mitochondrial reprogramming across OC histologic subtypes, and the dual protumor and antitumor roles of ROS, with particular emphasis on the interplay between ferroptosis and immune regulation. Furthermore, we highlight emerging pro-oxidant therapies, ferroptosis inducers, nanodelivery systems, and immune-based combinatorial strategies. Ultimately, we propose a dynamic ROS modulation framework that advocates for precise, personalized pro-oxidant or antioxidant interventions based on each patient's tumor subtype, real-time redox state, and TIME characteristics, offering a robust translational path for next-generation precision oncology in OC.

PMID:
42600958
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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