Boosting T cell antioxidant capacity: A strategic approach to overcome immunosuppression in solid tumors

Adoptive T cell therapy faces significant hurdles in solid tumors due to the immunosuppressive tumor microenvironment (TME), wherein aberrant accumulation of reactive oxygen species (ROS) serves as a critical driver of therapeutic resistance. Conventional systemic antioxidant strategies are constrained by their non-selectivity and potential to disrupt physiological ROS signaling. Here, we systematically delineate the inherent heterogeneity among T cell subsets-including effector, memory, and regulatory T cells-with respect to metabolic preferences, mitochondrial dynamics, and antioxidant gene expression, revealing their divergent susceptibilities to oxidative stress. Furthermore, the intricate interplay between ROS and diverse immune subsets within the TME, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), collectively orchestrates an immunosuppressive network that underscores the imperative for selective intervention. Building upon this foundation, we propose a multi-layered intervention framework encompassing: (i) reinforcement of intrinsic antioxidant defenses; (ii) metabolic reprogramming to potentiate redox capacity; and (iii) nanomaterial-based remodeling of the pro-oxidative microenvironment. Notably, we introduce the first combinatorial framework centered on nanomaterial-enabled TME modulation integrated with T cell-intrinsic orchestration-a strategy rationally designed to synergistically preserve stem-like memory phenotypes and augment antitumor persistence through multidimensional redox regulation. This framework emphasizes the profound coupling between metabolic and redox homeostasis while critically addressing current challenges, including cellular selectivity, therapeutic windows, and the risk of reductive stress. By providing an integrated mechanistic roadmap and a clear translational trajectory, this review aims to guide future efforts toward subset-selective interventions, spatiotemporally controlled redox modulation, and synergistic integration with existing immunotherapies, ultimately advancing adoptive T cell therapy for solid tumors.