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Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy.Pelly, Victoria S; Moeini, Agrin; Roelofsen, Lisanne M; orcid: 0000-0001-7686-1614; Bonavita, Eduardo; orcid: 0000-0003-2335-5827; Bell, Charlotte R; orcid: 0000-0001-8653-2291; Hutton, Colin; orcid: 0000-0003-2254-1038; Blanco-Gomez, Adrian; orcid: 0000-0002-1956-088X; Banyard, Antonia; Bromley, Christian P; orcid: 0000-0001-6203-6891; Flanagan, Eimear; et al. (2021-05-24)Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from non-responders shortly following treatment and identified acute IFN-γ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot.