Background: IRF2BP2 (Interferon Regulatory Factor-2-Binding Protein-2) is a transcriptional co-factor involved in gene regulation in multiple biological contexts. Our group previously identified IRF2BP2 as a NFAT1 transcription factor co-repressor with a role in T lymphocyte activation and differentiation. Upon activation, CD8 T cells differentiate into effector cells and memory cells. Cytotoxic CD8 T cells (CTLs) play a central role in eliminating tumor cells. During chronic antigen stimulation, TCD8 cells can acquire a phenotype known as T cell exhaustion, characterized by impaired effector function. Importantly, exhausted T cells remain responsive to functional rescue, representing key targets for immunotherapy. Understanding the transcriptional mechanisms that regulate effector, memory, and exhausted CD8 T cell states is therefore critical. In this context, IRF2BP2 may play an important role in controlling CD8 T cell fate and function. Objective and Methods: The main objetive of this study is to evaluate the role of IRF2BP2 in the activation and differentiation of the CD8 T cell response in vivo. For better understanding the involvement of IRF2BP2, we generated a conditional transgenic mice that overexpresses IRF2BP2 in T lymphocytes, LCK-Cre Rosa26 Stop-flox IRF2BP2-IRES-EGFP (IRF2BP2 TKi). To evaluate the effect of IRF2BP2 on CD8 T cell differentiation, we assessed effector and memory profile using in vitro skewed cell culture. To validate the in vitro findings in a physiological context, we investigated the role of IRF2BP2 in vivo using experimental models of lymphocytic choriomeningitis virus (LCMV) infection and B16F10 melanoma. Results: Naive IRF2BP2 TKi mice showed a reduction in T cell population in peripheral organs. IRF2BP2 TKi animals displayed increased percentage of CD8+CD44+ cells, which suggests that these animals present an increase of effector cells.  Cells from IRF2BP2 TKi animals revealed an increased percentage of CD8+CD44+ population and an increase of granzyme B in effector cultures. In memory culture, cells from IRF2BP2 TKi animals revealed an increase of IFN-g and Granzyme B.  We assessed by qRT-PCR the master transcription factors involved CD8 T cell differentiation and observed an increase of Tbet and Prdm1 in effector cells. These data suggested a positive regulation of some effector molecules by IRF2BP2 and suggested these cells present a phenotype of effector cells. Considering that IRF2BP2 influences the production of effector molecules, we evaluated CD8 T cells response in a model of chronic viral infection with LCMV. The animals were challenged with sublethal dose of the LCMV clone13. Twenty days after infection, we observed a decrease of PD-1 in CD8 virus specific cells of IRF2BP2 TKi mice. Furthermore, IRF2BP2 TKi animals displayed enhanced tumor protection in a B16 melanoma model, accompanied by a reduction in the exhausted profile (decrease of PD1+ and PD+Tim3+ lymphocytes), a key hallmark associated with improved immunotherapeutic outcomes. Conclusions and Implications: Taken together, these data suggest a role for IRF2BP2 protein in regulating the balance between CD8 T cell activation and hyporesponsiveness, with the potential to enhance long-term tumor control in immunotherapy settings, that may serve a novel therapeutic targets in anti-cancer strategies