Targeting EP2/EP4-driven expansion of suppressive VSIG4high macrophages overcomes immunotherapy resistance in colorectal cancer
<h2>Summary</h2> 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<sup>high</sup> TAM subset and enhances cytotoxic CD8<sup>+</sup> T cell-mediated CRC tumor elimination. Mechanistically, TP-18 dampens the expression of VSIG4 by blunting EP2/EP4-Gαs-PKA signaling. Notably, VSIG4<sup>high</sup> TAMs from CRC-tumor-bearing mice display robust immunosuppressive features, and similar VSIG4<sup>high</sup> 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<sup>high</sup> TAMs as a promising therapeutic strategy to overcome immunotherapy resistance.
Authors
- Naijipu Abuduaini (ORCID: https://orcid.org/0009-0005-7849-7648)
- Weiqiang Lü (ORCID: https://orcid.org/0000-0003-1349-6597)
- Ruth Nussinov (ORCID: https://orcid.org/0000-0002-8115-6415)
- Guichao Li (ORCID: https://orcid.org/0000-0003-4911-5995)
- Xiaolei Chai
- Esteban Ballestar (ORCID: https://orcid.org/0000-0002-1400-2440)
- Weiwei Rui
- Zhiyuan Cheng
- Bo Feng
- Ning Zhu
- Jun Wu
- Ke Quan
- Jiacheng He
- Limin Du
- Yao Zhang
- Feixiong Cheng
- Wei Wang (ORCID: https://orcid.org/0009-0003-5503-6537)
- Jingbo Wu
- Siqi Ma
- Xinyu Yang
- Mengru Wang
- Yang Wang (ORCID: https://orcid.org/0009-0006-6828-7185)
- Dawei Li
- Mengxian He
- Linlin Yang
- Mingyao Liu
Institutions
- Tel Aviv University (IL)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Ruijin Hospital (CN)
- Cleveland Clinic Lerner College of Medicine (US)
- Zhengzhou University (CN)
- Josep Carreras Leukaemia Research Institute (ES)
- Fudan University Shanghai Cancer Center (CN)
- Zhejiang Cancer Hospital (CN)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Case Western Reserve University (US)
- East China Normal University (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-05-28
- DOI
- https://doi.org/10.1016/j.celrep.2026.117450
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- National Cancer Institute