biostudies-literatureWu ZNational Natural Science Foundation of Chinae155224https://www.ebi.ac.uk/biostudies/studies/S-EPMC8970670biostudies-literatureUnknown132(7)The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived ROS triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and rThe Journal of clinical investigationSENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.PMC897067081930040,31922025,32170908Wu ZHan QDing RHu ZZhao RHuang HTeng XLZou QYe YWang ZYu XfalseSENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived ROS triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and r2022-01-01T00:00:00Z2022 Apr2026-05-31T06:02:01.86Z2025-02-19T01:54:56.715ZS-EPMC89706703514342110.1172/JCI155224