It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age‐related tumorigenesis. T‐cell senescence plays a critical role in immunosenescence and is involved in the age‐related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T‐cell phenotype acquire an natural killer (NK) cell‐like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6–10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin‐deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin‐deficient senescent CD8+ T cells. Furthermore, Menin‐deficient CD8+ T cells can eliminate tumor cells in an antigen‐independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK‐like innate immune functions, such as antigen‐independent cytotoxic activity.

CD8+ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8+ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8+ T‐cell differentiation and the antitumor immune response. In a murine tumor‐bearing model, an increased tumor size and decreased survival rate were observed in T‐cell‐specific Utx KO (Utx KO) mice compared with wild‐type (WT) mice. The number of CD8+ T cells in tumor‐infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8+ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8+ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8+ T cells to tumor sites, was substantially decreased in Utx KO CD8+ T cells. These findings suggest that Utx promotes CD8+ T‐cell‐dependent antitumor immune responses partially through epigenetic regulation of the effector function.