Depletion of stubborn Tregs surviving lymphodepletion augments adoptive T-cell therapy (ACT). (A) Systemic chemo- or radiation therapy before ACT enhances the function of adoptively transferred T cells by removing cellular “sinks” for homeostatic cytokines, reducing the number of regulatory T cells (Tregs), and activating host dendritic cells by triggering the release of endogenous Toll-like receptor (TLR) agonists through mucosal injury. However, surviving Tregs undergo robust homeostatic expansion limiting the full antitumor potential of transferred T cells. (B) Concurrent depletion of these “stubborn” Tregs using antibodies targeting CD25, the IL-2Rα chain, unleashes transferred T-cell function providing for optimal tumor regression.