In recent years, a growing interest has been garnered in the restoration of anti-tumor immunity in cancer treatment. As a potential therapeutic strategy, the benefits of immune checkpoint inhibitors have been demonstrated in many clinical studies. Although various methods have been applied to suppress immune checkpoints to boost anti-tumor immunity, including immune checkpoint inhibitors, there still exist unmet clinical needs to improve the response rate of cancer treatment. Here, we show that acetate suppresses the expression of a ligand for immune checkpoint, poliovirus receptor (PVR/CD155), in colon cancer cells. We demonstrated that acetate treatment in the cancer cells enhances effector responses of CD8+ T cells via reduced expression of PVR/CD155. We also found that acetate reduces the expression of PVR/CD155 through the PI3K/AKT pathway deactivation. Together, we demonstrated that acetate mediated the expression of PVR/CD155 in cancer cells that might potentiate the anti-tumor immunity in the cancer microenvironment. Our findings indicate that maintaining particular acetate concentrations could represent a complementary treatment strategy in current cancer treatment.