Objective

FOXP3 is a multifaceted transcription factor with a major role in the control of immune homeostasis mediated by T regulatory cells (Treg). In addition to its role in Treg cells, FOXP3 can be transiently expressed in effector T cells after TCR stimulation and induce an status of hyporesponsivenes. These finding suggest that FOXP3 might act as an intracellular immune checkpoint that may hinder protective role of T cells in pathologies such as viral infections or cancer. The capacity of FOXP3 to bind DNA is assisted by a number of FOXP3 cofactors and by multimerization. Thus, those strategies able to inhibit a particular interaction with FOXP3, or able to modify the FOXP3 interactome might have important consequences on its modulatory activity. We have identified synthetic peptides and small molecules able to enter into the cells, bind to Foxp3 and inhibit FOXP3 dimerization, nuclear translocation or its interaction with other transcription factors such as Runx1 or NFAT improving T cell effector functions in vitro and in vivo. These inhibitors might be considered in the design of new antitumor immunotherapies.