Downregulation of Ezh2 promotes the differentiation of short-lived effector CD8 T cells and weakens antitumor immunity

T-cell function is epigenetically regulated, however its precise role in tumor immunity is not fully understood. Ezh2 promotes transcriptional silencing through trimethylation of histone H3K27. We previously reported that the methylation level of histone H3K27 decreases in terminally differentiated and senescent T cells. In this study, we analyzed the role of Ezh2 in the differentiation of effector CD8⁺ T cells and antitumor immunity. In a mouse tumor model, T-cell-specific Ezh2 KO mice exhibited reduced initial tumor growth compared to wild-type (WT) mice, but tumors grew rapidly after day 7. The number of CD8⁺ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Ezh2 KO mice. We found that although the expression of effector molecules was rapidly increased in Ezh2 KO CD8⁺ T cells compared to WT cells, apoptotic cell death was also rapidly induced after activation. RNA-sequencing revealed that the expression of effector signature genes was upregulated in Ezh2 KO effector CD8⁺ T cells, along with the expression of apoptosis-related genes. These findings suggest that Downregulation of Ezh2 promotes the differentiation of short-lived effector CD8 T cells and weakens antitumor immunity. These findings suggest that downregulation of Ezh2 promotes the differentiation of short-lived effector CD8⁺ T cells and impairs sustained antitumor immunity. Maintaining appropriate levels of H3K27 trimethylation may be essential for the long-term persistence of effective antitumor T cell responses.