Yao Zhang, Xinyu Yang, Zhiyuan Cheng, Mengxian He, Jiacheng He, Wei Wang, Ke Quan, Siqi Ma, Jun Wu, Xiaolei Chai, Naijipu Abuduaini, Bo Feng, Weiwei Rui, Yang Wang, Jingbo Wu, Dawei Li, Guichao Li, Limin Du, Mengru Wang, Linlin Yang, Ning Zhu, Ruth Nussinov, Feixiong Cheng, Esteban Ballestar, Mingyao Liu, Weiqiang Lü
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 VSIG4 high 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, VSIG4 high TAMs from CRC-tumor-bearing mice display robust immunosuppressive features, and similar VSIG4 high 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 VSIG4 high TAMs as a promising therapeutic strategy to overcome immunotherapy resistance.