The distinct roles of ROS in tumor immunity: from mechanisms to immunotherapeutic applications
Jiayi Li, Chen Huang, Pan Tang, Ruiyan Wu, Quanyou Wu, Chenliang Zhang
Abstract
Reactive oxygen species (ROS) are crucial signaling molecules that regulate diverse biological processes. In cancer, this duality gives rise to a central paradox. Moderate ROS levels support tumor proliferation and foster an immunosuppressive microenvironment, whereas excessive ROS can be therapeutically leveraged to trigger immunogenic cell death (ICD). Crucially, the outcome on immune cells, whether activation or exhaustion, is dictated by the subcellular localization and kinetics of ROS generation. This review critically examines this "ROS-Immune Mismatch," a new framework that highlights the differential redox sensitivities between tumor cells and key immune subsets. This differential sensitivity, where cytotoxic T cells (Teffs) are exhausted and immunosuppressive cells like regulatory T cells (Tregs) thrive, is a fundamental mechanism of immune evasion. We further analyze how emerging immunotherapies seek to exploit these redox dependencies to enhance therapeutic efficacy. Finally, we discuss major translational challenges, including off-target oxidative toxicity and redox heterogeneity within the tumor microenvironment (TME), and highlight future directions, such as intelligent nanomedicine and redox-reprogrammed cellular therapies, as promising strategies for next-generation ROS-targeted immunomodulation.