A study published in Nature Immunology by Van Andel Institute and collaborators reveals prostacyclin receptor PTGIR as a novel immune checkpoint that regulates CD8+ T cell exhaustion within the tumor microenvironment. PTGIR engagement reduces T cell activity via lipid-protein signaling, distinct from classical protein-protein immunoregulatory pathways. Elevated NRF2 transcription factor levels amplify PTGIR expression, intensifying T cell functional decline. Targeting this checkpoint opens innovative avenues for cancer immunotherapy to rejuvenate T cell responses and improve anti-tumor immunity.