A better understanding of the fundamental mechanisms underlying tumor immune evasion is critically for the development of new immunotherapy strategies aimed to restore/stimulate effective antitumor immune response in a larger number of patients. We previously reported a pivotal role for the actin cytoskeleton in mediating cancer cell resistance to natural killer (NK) cell-induced cell death. We showed that, upon NK cell attack, a massive accumulation of actin near the immunological synapse (the interface between the NK cell and its target) rapidly takes place in resistant tumor cells. We termed this process “actin response” and provided evidence that it protects NK cell-conjugated target cells from undergoing apoptosis by preventing intracellular accumulation of NK cell-secreted cytotoxic molecules. Recently, we established that the actin response is a fundamental feature of immune evasion conserved across different malignancies and induced in response to AG-specific cytotoxic T lymphocyte attack. However, the mechanism underlying actin response-mediated immune evasion remains unclear. Based on our unpublished data, we will explore the possibility that the actin response acts as a “physical barrier” altering the structure and activity of the immunological synapse. Using state-of-the-art live cell imaging approaches, we will depict the structural and functional immunological defects caused by the actin response during the early steps of immune effector cell-tumor cell interaction, such as alterations of the immunological synapse organization and increase of inhibitory immune checkpoint molecule density at the cell-cell contact points. Finally, we aim at examining the prevalence of the actin response in pathological samples.