Cell Rep

Tumor-associated macrophages (TAMs) pose a significant obstacle to successful cancer immunotherapy in colorectal cancer (CRC). Herein, we demonstrate that genetic deletion of PGE2 receptors EP2/EP4 markedly sensitizes CRC tumors to anti-PD-1 therapy. We then report the development of TP-18, a potent and orally available dual EP2/EP4 antagonist. TP-18 treatment effectively depletes a highly immunosuppressive VSIG4high TAM subset and enhances cytotoxic CD8+ T cell-mediated CRC tumor elimination. Mechanistically, TP-18 dampens the expression of VSIG4 by blunting EP2/EP4-Gαs-PKA signaling. Notably, VSIG4high TAMs from CRC-tumor-bearing mice display robust immunosuppressive features, and similar VSIG4high populations are also detected in patients with CRC and other cancers. Importantly, TP-18 improves the therapeutic efficacy of anti-PD-1 therapy in CRC mouse models and in patient-derived tumor immune organoids. Collectively, our findings establish targeting of EP2/EP4-driven expansion of VSIG4high TAMs as a promising therapeutic strategy to overcome immunotherapy resistance.