RESUMEN
T cell dysfunctionality prevents the clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB). However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here we innovate an in vitro model system of stable human T cell dysfunction and show that chronic TGFß1 signaling in posteffector CD8+ T cells accelerates their terminal dysfunction through stable epigenetic changes. Conversely, boosting bone morphogenetic protein (BMP) signaling while blocking TGFß1 preserved effector and memory programs in chronically stimulated human CD8+ T cells, inducing superior responses to tumors and synergizing the ICB responses during chronic viral infection. Thus, rebalancing TGFß1/BMP signals provides an exciting new approach to unleash dysfunctional CD8+ T cells and enhance T cell immunotherapies.