Anti-tumor T cell responses are limited by immunosuppressive mechanisms, including inhibitory receptors (checkpoints), metabolic competition and suppression by regulatory T cells. New therapies aiming at reactivation of antigen-specific T cells by overcoming immune suppression resulted in dramatic improvements in the outcome for some patients. However, what determines success or failure of immunotherapy is still poorly understood. Recent studies from our group and others have shown that effector T cell responses during chronic infection and cancer are maintained and can be boosted by memory-like T cells, which express high amounts of the inhibitory receptor PD1 while also displaying memory T cell characteristics. These cells have been termed ‘exhausted memory-like’ T cells or TMEX.* In this project, we will identify molecular pathways that control the development of TMEX and could be harnessed to improve patient outcome. Our published and preliminary work identified a number of molecules that are linked to the modulation of cytokine responsiveness, T cell receptor (TCR) signaling and cellular metabolism that control the magnitude and dynamics of T cell responses to chronic infection and tumors. This includes the transcriptional regulator Id3, expression of which we found specifically identified TMEX both in chronic infection and tumors. Id3+ TMEX differ dramatically from their Id3- ‘exhausted’ T cell (TEX) counterparts in phenotype and function. They also display substantially elevated mitochondrial metabolism, which we found was required for the beneficial outcomes of checkpoint inhibition. In the course of this study, we will examine pathways that control the development and maintenance of TMEX, devise strategies to promote T cell responses and aim to correlate our findings with patient outcomes. This work will provide fundamental insights into the biology of this essential cell type with far reaching implications for our understanding of T cell responses in chronic infection and cancer.