Oxidative stress in CAR-T cell therapy: Mechanistic insights and redox-targeted interventions

Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in hematological malignancies but faces significant challenges in solid tumors due to the immunosuppressive and pro-oxidant tumor microenvironment (TME). Elevated levels of reactive oxygen species (ROS) in the TME-produced by both tumor and stromal cells-contribute to DNA damage, mitochondrial dysfunction, and altered signaling pathways in CAR-T cells, ultimately compromising their antitumor functions. Moreover, ROS act synergistically with other immunosuppressive mechanisms, further suppressing CAR-T cell activity. To circumvent these barriers, approaches such as genetic engineering to bolster antioxidant systems, metabolic reprogramming, CAR design optimization, and innovations including pharmacological or nanotechnology-based ROS scavenging strategies are being examined. This review comprehensively evaluates the mechanisms by which oxidative stress compromises CAR-T cell therapy in solid tumors and highlights redox-targeted interventions, providing critical insights to optimize therapeutic outcomes while maintaining physiological ROS balance.