Triptolide decreases tumor-associated macrophages infiltration and M2 polarization to remodel colon cancer immune microenvironment via inhibiting tumor-derived CXCL12

Colon cancer is a common and deadly human digestive tract malignant tumor with poor prognosis. Immunotherapy has elicited tremendous success as a treatment modality for multiple solid tumors. Triptolide is extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. F which shows various pharmacological actions including antitumor, anti-inflammatory, antimicrobial, antifibrosis, and antirheumatic. However, the influence of triptolide treatment on remodeling tumor immune microenvironment is still unknown in colon cancer. This study was aimed to investigate the therapeutic effect of triptolide treatment on colon cancer and the impact on tumor immune microenvironment and its underlying mechanism. We used CT26 subcutaneous tumors to conduct in vivo experiments and HT29, CT16, and Raw264.7 cells to perform in vitro assays. Triptolide had a therapeutic effect against colon cancer in vivo. Triptolide treatment distinctly inhibited the proliferation of colon cancer cells and induced apoptosis in vitro. In colon cancer immune microenvironment, triptolide treatment decreased the infiltration of tumor-associated macrophages through downregulating tumor-derived CXCL12 expression via nuclear factor kappa B and extracellular signal-regulated protein kinases 1 and 2 axis to remodel the immune microenvironment. Triptolide-educated colon cancers retarded the macrophages polarize to anti-inflammatory M2 status by decreasing the expression of Arg-1, CD206, and interleukin-10. Moreover, triptolide inhibited the migration of colon cancer cells via decreasing vascular endothelial growth factor expression. Our results identified the role of triptolide treatment in remodeling colon cancer immune microenvironment along with the distinct cytotoxicity function against colon cancer cells, which may provide the evidence for triptolide treatment in clinical.