Phillygenin regulates the colorectal cancer tumor microenvironment by inhibiting hypoxia-inducible factor 1 alpha.

The tumor microenvironment (TME) is important in the recurrence and metastasis of colorectal cancer (CRC). Phillygenin is an effective component of Forsythiae fructus that has long been used in cancer therapy. The mechanism by which phillygenin regulates the TME remains unknown. Methods and Results: A co-culture system of CRC cells and Jurkat T cells was used to simulate the TME in vitro. Network pharmacology and Human XL cytokine arrays were used to preliminarily evaluate the role of phillygenin in the TME. The target of phillygenin was determined using transfection of plasmid-producing overexpression of hypoxia-inducible factor 1 alpha (HIF-1α) overexpression or abrogated HIF-1α expression via short hairpin RNA plasmid. The therapeutic effect of phillygenin in vivo was assessed in a subcutaneous tumor mouse model. In vitro, phillygenin enhanced the immune response of T cells and prevented the immune escape of cancer cells via the inhibition of HIF-1α. Phillygenin upregulated interleukin (IL)-2 and downregulates IL-10 and FOXP3 in Jurkat T cells co-cultured with CRC cells. Phillygenin inhibited expressions of HIF-1α, transforming growth factor-beta, vascular endothelial growth factor, and CD31 in CRC cells cultured alone or with Jurkat T cells. Phillygenin considerably suppressed tumor growth and improved the TME in vivo. Conclusions: Phillygenin can enhance the immune response and inhibit angiogenesis in the TME in CRC by inhibiting HIF-1α.

Supplementary information: The online version contains supplementary material available at 10.1007/s10616-024-00679-2.