2. Academic Validation
  3. Norcantharidin promotes M1 macrophage polarization and suppresses colorectal cancer growth

Norcantharidin promotes M1 macrophage polarization and suppresses colorectal cancer growth

  • Acta Pharmacol Sin. 2025 May 20. doi: 10.1038/s41401-025-01578-8.
Xiao-Man Wei # 1 2,  Si-Cheng Lu # 2 3,  Liu Li # 1 2,  Ying-Jie Gao 1 2,  Jun-Yi Wang 2 4,  Song-Yang Xi 1 2,  Ling-Yu Linda Ye 3,  Wei-Xing Shen 5 6,  Mian-Hua Wu 7 8,  Dayue Darrel Duan 9 10,  Hai-Bo Cheng 11 12
Affiliations

Affiliations

  • 1 The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China.
  • 3 School of Integrative Medicine of Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
  • 5 The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210023, China. weixingshen@njucm.edu.cn.
  • 6 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China. weixingshen@njucm.edu.cn.
  • 7 The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210023, China. wmh7001@163.com.
  • 8 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China. wmh7001@163.com.
  • 9 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China. dduan@medicine.nevada.edu.
  • 10 Department of Pharmacology, University of Nevada Reno School of Medicine, Reno, NV, 89557, USA. dduan@medicine.nevada.edu.
  • 11 The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210023, China. haibocheng@njucm.edu.cn.
  • 12 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China. haibocheng@njucm.edu.cn.
  • # Contributed equally.
PMID: 40394236 DOI: 10.1038/s41401-025-01578-8
Abstract

Colorectal Cancer (CRC) is characterized by an immunosuppressive and inflammatory microenvironment, thus responds poorly to therapy. Previous studies show that norcantharidin (NCTD), a demethylated cantharidin (CTD) derived from Mylabris, exerts high efficacy in treating various cancers. In this study we investigated the antitumor effects of NCTD against CRC and the underlying mechanisms. Subcutaneous CRC models were established in balb/c mice using mouse colorectal Cancer cell line CT26 and in balb/c nude mice using human colorectal Cancer cell line HCT116. The mice were administered NCTD (2 or 4 mg·kg-1·d-1, i.p.) for 14 days. We showed that NCTD dose-dependently reduced the tumor growth in both the CRC models. Furthermore, NCTD markedly increased M1 macrophage infiltration in tumor tissue in both the CRC models. NCTD-induced macrophage M1 polarization was confirmed by flow cytometry and qPCR assays in both THP-1 cell-derived and RAW264.7 macrophage models in vitro. We demonstrated that NCTD (20, 40 μM) dose-dependently increased CSF2 secretion from CRC cells and macrophages, and suppressed the JAK2/STAT3 signaling pathway in CRC cells. Concurrently, NCTD (10-40 μM) dose-dependently inhibited CRC cell proliferation, invasion and migration in vitro. In conclusion, this study provides new evidence for the effects of NCTD against CRC and elucidates its antitumor mechanisms through remodeling the inflammatory microenvironment via CSF2-mediated macrophage M1 polarization and inhibiting JAK2/STAT3 phosphorylation in CRC cells.

Keywords

CSF2; JAK2/STAT3 pathway; M1 macrophage; colorectal cancer; norcantharidin; tumor microenvironment.

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