Oxidative Stress and DNA Epigenetic Modifications in Cancer: Mechanisms and Targeted Therapeutics

ABSTRACT Oxidative stress, defined as an imbalance between the production and clearance of reactive oxygen species (ROS), is not merely a reflection of metabolic or microenvironmental stress but an active signaling and regulatory hub in cancer. ROS function as key signaling molecules that drive tumorigenesis, metabolic reprogramming, and epigenetic remodeling. However, a systematic view of the spatiotemporally organized, bidirectional crosstalk between ROS and the DNA epigenetic machinery, particularly under conditions such as hypoxia, remains incomplete. This review synthesizes current understanding of this bidirectional axis. We detail how ROS reshape the DNA epigenetic landscape by modulating DNA methyltransferases and ten‐eleven translocation family protein (TET) dioxygenases, altering profiles of 5‐methylcytosine and its oxidized derivatives, and how epigenetic modifications in turn regulate ROS homeostasis through antioxidant and metabolic pathways. We further explore the cascade regulation of this interaction within the hypoxic tumor microenvironment and evaluate combined intervention strategies targeting both redox and epigenetic mechanisms. Emerging therapeutic avenues are highlighted, including spatiotemporally controlled ROS modulation, CRISPR‐based epigenome editing, ROS‐responsive proteolysis‐targeting chimeras, artificial intelligence (AI)‐driven multi‐omics prediction, and tissue‐specific delivery platforms. By integrating these insights, this review provides a framework for developing ROS‐guided precision epigenetic reprogramming strategies, offering novel therapeutic opportunities in cancer.