Abstract CD8+ tumor infiltrating lymphocytes (TILs) are not only critical for the anti-tumor immune response in solid tumors, but also in the success of adoptive cell therapies and in immune check point blockade (ICB) treatments. CD8+ TILs have been shown to be heterogeneous, and in time to progress to a terminally exhausted state, with no ability to respond, and resistant to reprograming by ICB. It remains of critical importance to understand the biology, transcriptional programs and epigenetic control of the progression of the precursors, which have high functional potential and stemness, to the terminally exhausted CD8+ TILs. Cells with characteristics of memory have been identified in tumors and their presence is associated with a positive outcome. Recently a memory CD8+ T cell population has been identified, located predominantly in tumor draining LNs and showing an efficient antitumor response upon recall. However, little it is known about tumor memory cells, their response, transcriptional and epigenetic control, as well as their failure in recurrent tumors associated with relapse. Our preliminary data show that ablation of the transcription factor BCL11B in TILs unleashes stemness at the same time with the effector programs, but restricts exhaustion, providing TILs with increased ability to promote a more efficient anti-tumor response compared to WT counterparts. In addition, depletion of BCL11B in TILs from a patient who did not respond to TIL adoptive cell therapy, improved their cytolytic activity. We hypothesize that BCL11B plays a central role in controlling essential programs of TILs, including stemness, effector and exhaustion. Our preliminary data also show BCL11B KO tumor memory cells outperform WT memory cells in a recall response to tumors. Using scRNAseq and genome-wide histone marks analyses we will establish the programs and epigenomic landscape controlled by BCL11B in mouse TILs. In addition, we will investigate the programs and the epigenomes