A collaborative study from Van Andel Institute uncovers PTGIR, a prostacyclin receptor, as a novel immune checkpoint regulating CD8+ T cell exhaustion in cancer. PTGIR engagement by prostacyclin in the tumor microenvironment suppresses T cell activity, impairing antitumor immunity. The receptor’s regulation by the NRF2 transcription factor further elucidates mechanisms of immune suppression. Targeting this lipid-protein checkpoint could offer innovative immunotherapeutic strategies distinct from classical protein-based checkpoints, potentially enhancing cancer treatment efficacy.