Understanding the mechanisms of immunosuppression development has formed the basis for modern cancer immunotherapy. However, some immunotherapies, including immune checkpoint inhibitors, have demonstrated limited efficacy in solid tumors. It is noted that additional activation of the immune system after immunotherapy increases the risk of developing autoimmune diseases. Reprogramming T-cell metabolism is critical for enhancing the antitumor immune response. We have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. This approach shown high efficiency on immune cells isolated from mouse bone marrow. We hypothesized that reprogramming of spleen CD8⁺ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8⁺ T-cells isolated from the spleen of C57BL/6 mice (rsCD8⁺T-cells). The rsCD8⁺T-cells actively migrated into the lungs of mice with Lewis lung carcinoma (LLC) after intravenous injection and in vitro demonstrated high survival, and targeted elimination of cancer stem cell (CSC). In orthotopic LLC model, cell therapy with rsCD8⁺T-cells increased the amount of proliferating CD8⁺ and CD4⁺ T-cells in blood and lung tissue of C57BL/6 mice. In addition, the amount of CSC decreased in the blood and lung of mice treated with rsCD8-T-cells. A morphological study revealed a decrease in the number of metastases in the lung tissue. Thus, reprogramming increases the antitumor activity of spleen CD8⁺ T-cells; the antitumor effects of rsCD8⁺T-cells in vivo are based on the activation of the host immune response by increasing the populations of CD8⁺ and CD4⁺ T-cells and apoptosis of CSCs.