Cyclooxygenase (COX)-dependent production of prostaglandin E2 (PGE2) by various tumors drives malignant growth by successfully evading type I interferon and/or T-cell-dependent tumor elimination. Genetic ablation of COX in tumor cells, such as in BrafV600E mouse melanoma, NrasG12D melanoma, and breast or colorectal cancer cells, enables immune control and shifts the tumor inflammatory profile toward classic anti-cancer immune pathways. COX inhibitors synergize with checkpoint blockade therapy, suggesting that they could be useful adjuvants for immune-based therapies in cancer patients. The COX-dependent inflammatory signature is conserved across mouse and human cancer biopsies, indicating that COX activity is a driver of immune suppression across species.Cyclooxygenase (COX)-dependent production of prostaglandin E2 (PGE2) by various tumors drives malignant growth by successfully evading type I interferon and/or T-cell-dependent tumor elimination. Genetic ablation of COX in tumor cells, such as in BrafV600E mouse melanoma, NrasG12D melanoma, and breast or colorectal cancer cells, enables immune control and shifts the tumor inflammatory profile toward classic anti-cancer immune pathways. COX inhibitors synergize with checkpoint blockade therapy, suggesting that they could be useful adjuvants for immune-based therapies in cancer patients. The COX-dependent inflammatory signature is conserved across mouse and human cancer biopsies, indicating that COX activity is a driver of immune suppression across species.