The upregulation of inhibitory molecules is a major driver of immune escape in cancer. In contrast, less is known about the regulation of T cell activating receptors within the tumor microenvironment. It was recently shown that tumor-derived CD155 induces downregulation of the activating receptor CD226 in mouse and human CD8+ T cells (Braun et al., 2020). The study demonstrated that phosphorylation of CD226 at tyrosine 319 (Y319) induced internalisation, and proteasomal degradation of CD226 rendering CD8+ T cells dysfunctional and thus leading to impaired anti-tumor immunity and resistance to cancer immunotherapy. Accordingly, mutation of Y319 led to increased CD226 surface expression and enhanced the efficacy of cancer immunotherapies. However, the mechanism how increased CD226 expression levels in T cells contributes to enhanced T cell immunity remains elusive. Additional, CD226 is important for T cell activation and cell-cell interaction, it needs to be clarified how the mutation of CD226 in T cells influences T cell fitness and differentiation. Thus, the central aim of the project is to understand the importance of CD226 for T cell interactions with activating immune cells and target cells (tumor cells) which might improve or influence T cell activation, differentiation and fitness of anti-tumoral T cell response.