Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor.

Live regulatory T cells (T _reg cells) suppress antitumor immunity, but how T _reg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor T _reg cells undergo apoptosis, and such apoptotic T _reg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic T _reg -cell-mediated immunosuppression. Mechanistically, apoptotic T _reg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A _2A pathways. Apoptosis in T _reg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor T _reg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls T _reg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.