Research over the past decade in tumor immunology has shown that immune reactivity to tumor antigens can decrease tumor growth in experimental models. These observations have been translated into clinical studies involving both passive and active forms of immunotherapy. Immunotherapy, an alternative treatment for cancer, is confronted to a major hurdle: tumor escape of specific lysis. Cancer antigen-specific cytotoxic T lymphocytes (CTL) are the major effectors used in immunotherapy against cancer cells. However, large established tumors are usually not fully controlled by CTL. These effector cells could indeed have a dual activity, which allow cancer cells to escape destruction. In this review, we will focus on the essential role of the p53 tumor suppressor gene in the dynamic regulation of tumor cell death induced by cytotoxic T lymphocytes and the involving of structural changes of cytoskeleton in the acquisition of tumor resistance.