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Immune intervention has become a nontoxic approach to control advanced cancer.A key to device an effective tumor immunotherapy is to overcome the mechanisms of peripheral tolerance exploited by tumor for immune evasion.CD4+FoxP3+ regulatory T cells (Tregs) play a nonredundant role in the maintenance of immunological homeostasis and in the prevention of autoimmune disorders, and they also represent a major cellular mechanism in immune evasion by tumors.Elimination of Treg activity has become a novel therapeutic strategy to boost anti-tumor immune responses.The pleiotropic cytokine tumor necrosis factor-alpha (TNF) is a major participant in the initiation and orchestration of complex events in inflammation and immunity.The biological functions of TNF are mediated by two structurally related, but functionally distinct receptors, TNFR1 (or p55) and TNFR2 (or p75).TNF has well-documented proinflammatory effects.Nevertheless, we unexpectedly found that TNF through TNFR2 preferentially activated and expanded Tregs.Furthermore, TNFR2 was constitutively expressed by Tregs and the expression of this receptor was able to identify the maximally suppressive subset of Tregs.TNF was able to up-regulate the expression of TNFR2, as well as other co-stimulatory TNFRSF members, on Tregs.More recently, we reported that TNF-TNFR2 interaction was also critical for the phenotypic and functional stability of Tregs.Tumor infiltrating Tregs expressed high levels of TNFR2 and they are highly immunosuppressive cells.The decisive role of TNF-TNFR2 signaling in Treg homeostasis was shown by the profound reduction of Tregs in mouse stains genetically ablation of TNFR2 ligands or receptor or its signaling component.Our findings suggest that targeting TNF-TNFR2 pathway may represent a novel strategy to eliminate Treg activities in tumor patients and consequently enhance the efficacy of tumor immunotherapy or cancer vaccine.