Abstract
T cells are one of the most powerful weapons to fight cancer; however, T-cell exhaustion and dysfunction restrict their long-lasting function in antitumor immunity. B-cell lymphoma 6 (BCL6) has many functions in CD8 T cells; however, it is unclear how it regulates the effector function and exhaustion of CD8 cells. Overall, a low level of BCL6 mRNA in human cancer samples is associated with better outcomes, but high expression of BCL6 is specifically observed in cytotoxic CD8 T cells. We found that BCL6 deficiency in activated CD8 T cells enhanced tumor repression in multiple mouse models. More IL-2-expressing CD8 T cells and reduced proportions of exhausted or dysfunctional CD8 T cells were detected within tumors when Bcl6 was knocked out upon T-cell activation. Glycolysis was promoted, and GLUT3 expression was derepressed in BCL6-deficient CD8 T cells. The BCL6 inhibitor Fx1 promoted antitumor immunity in a T cell-dependent manner. These findings suggest a novel pathway to restore effector function of CD8 T cells by changing their energy use pathways to facilitate long-term tumor resistance.