Ginsenoside F4 inhibits colorectal cancer progression by boosting dendritic cell maturation and remodeling the tumor microenvironment

Immunotherapy that employs dendritic cells (DCs) to activate the patient's immune system has emerged as a promising therapeutic strategy to combat cancer; however, effective targeting agents are still limited. Ginsenoside F4, as a rare ginsenoside found in Panax ginseng, exhibits stronger antitumor and immunomodulatory activities than primary ginsenosides. However, its therapeutic effects on various diseases remain limited. To investigate the antitumor effect of Ginsenoside F4 and mechanism on the maturation of DCs in colorectal cancer (CRC). The changes in mature DC markers and cytokines generated after DCs were exposed to F4 were assessed using flow cytometry and enzyme-linked immunosorbent assay, respectively. The viability of CRC CT26 cells co-cultured with T lymphocytes was monitored by cell counting kit-8 assay. Furthermore, the histopathological characteristics and immune cell infiltration in tumor tissues of CT26-bearing mice were analyzed by hematoxylin-eosin and immunofluorescent staining. The expressions of apoptosis-relative proteins were detected by western blot assay. Treatment with F4 promoted the maturation of DCs, elevated the expressions of cluster of differentiation (CD) 83 and CD86, increased the secretion of interleukin (IL)-2, IL-10, and IL-12 p70, and upregulated the expressions of phosphorylated phosphoinositide 3-kinase, phosphorylated protein kinase B, and nuclear factor kappa-B (NF-κB) phosphorylated p65 in DCs, which enhanced antigen-specific CD8+ T-cell responses. However, these benefits could be reversed by the sphingosine-1-phosphate 1 (S1PR1) inhibitor fingolimod hydrochloride. Furthermore, oral administration with F4 inhibited tumor growth and increased DC and CD8+ T-cell infiltration in the tumor tissues of CT26-bearing mice. The results demonstrated that F4 inhibited the growth of CRC by maturing DCs through activating S1PR1-mediated phosphoinositide 3-kinase/protein kinase B and NF-κB pathways, which triggered the antitumor effects of CD8+ T cells. Therefore, F4 could serve as an antitumor immunomodulator for CRC treatment.