Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in...

Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8⁺ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8⁺ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.