Targeting EP2/EP4-driven expansion of suppressive VSIG4high macrophages overcomes immunotherapy resistance in colorectal cancer PMID: 42213779

ADC Targets in Oncology

2026-04-10

Targeting EP2/EP4-driven expansion of suppressive VSIG4high macrophages overcomes immunotherapy resistance in colorectal cancer

Cell Rep. 2026 Jun 23;45(6):117450. doi: 10.1016/j.celrep.2026.117450.

Yao Zhang ¹ , Xinyu Yang ² , Zhiyuan Cheng ² , Mengxian He ² , Jiacheng He ³ , Wei Wang ² , Ke Quan ² , Siqi Ma ² , Jun Wu ² , Xiaolei Chai ² , Naijipu Abuduaini ⁴ , Bo Feng ⁴ , Weiwei Rui ⁴ , Yang Wang ⁵ , Jingbo Wu ⁵ , Dawei Li ⁶ , Guichao Li ⁶ , Limin Du ⁷ , Mengru Wang ⁷ , Linlin Yang ⁷ , Ning Zhu ⁸ , Ruth Nussinov ⁹ , Feixiong Cheng ¹⁰ , Esteban Ballestar ¹¹ , Mingyao Liu ¹² , Weiqiang Lu ¹³

Affiliations

1. Center for Drug Discovery & Translational Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs and Haikou Key Laboratory of Li Nationality Medicine, School of Pharmaceutical Sciences, Hainan Medical University, Haikou, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
2. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
3. Center for Drug Discovery & Translational Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs and Haikou Key Laboratory of Li Nationality Medicine, School of Pharmaceutical Sciences, Hainan Medical University, Haikou, China.
4. Department of General Surgery and Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
5. Department of Urology and Department of Pathology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
6. Department of Colorectal Surgery, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
7. Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
8. Department of Medical Oncology and Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
9. Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
10. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
11. Epigenetics and Immune Disease Group, Josep Carreras Leukemia Research Institute, Badalona, Barcelona, Spain; Epigenetics in Inflammatory and Metabolic Diseases Laboratory, Health Science Center, East China Normal University, Shanghai, China.
12. Center for Drug Discovery & Translational Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs and Haikou Key Laboratory of Li Nationality Medicine, School of Pharmaceutical Sciences, Hainan Medical University, Haikou, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. Electronic address: [email protected].
13. Center for Drug Discovery & Translational Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs and Haikou Key Laboratory of Li Nationality Medicine, School of Pharmaceutical Sciences, Hainan Medical University, Haikou, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].

Abstract

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.

Keywords

CP: cancer; VSIG4; cancer immunotherapy; colorectal cancer; immunosuppression; immunotherapy resistance; prostaglandin E2; tumor immune microenvironment; tumor-associated macrophages.