Redox Reprogramming of the Tumor Microenvironment: Targeting Extracellular ROS to Restore Antitumor Immunity

Abstract

Reactive oxygen species (ROS) are central regulators of redox homeostasis yet exert paradoxical effects in cancer. While ROS overproduction can directly kill tumor cells, persistent oxidative stress in the tumor microenvironment (TME) paradoxically impairs antitumor immunity. Excess extracellular ROS oxidize critical thiols on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, disrupting immune synapse formation and effector function. ROS also compromise dendritic cells (DCs) antigen presentation via endoplasmic reticulum (ER) stress and lipid accumulation, and attenuate immunogenic cell death (ICD) by oxidizing damage-associated molecular patterns such as high mobility group box 1 protein (HMGB1) from its immunostimulatory disulfide form to an inert sulfonated state. These disruptions create a major barrier to effective immunotherapy. This review highlights that redox imbalance, rather than ROS abundance, determines therapeutic outcomes. We discuss mechanisms of ROS-mediated immune suppression, emphasizing oxidative modification of immune cell thiols, DC dysfunction, and disruption of danger signaling. Recent ROS-scavenging strategies, including small-molecule antioxidants and nanomedicine platforms, enable spatially and temporally controlled modulation of oxidative stress to restore immune competence. Emerging evidence supports strategies integrating transient ROS generation for tumor killing with sustained clearance to preserve immune signaling. We further outline challenges and future directions, including redox threshold identification, feedback-responsive systems, and biomarker-guided patient stratification. Precision redox modulation thus emerges as a promising approach to overcome immune suppression and enhance cancer immunotherapy durability.