Xie W, Li XJ, Zhong YS, Fang J, Qi H, Yang M, Ying HZ, Yu CH. Ginsenoside F4 inhibits colorectal cancer progression by boosting dendritic cell maturation and remodeling the tumor microenvironment. World J Gastrointest Oncol 2025; 17(9): 108892 [DOI: 10.4251/wjgo.v17.i9.108892]
Corresponding Author of This Article
Chen-Huan Yu, PhD, Dean, Senior Researcher, Hangzhou Institute of Medicine, Chinese Academy of Sciences, No. 150 Dongfang Street, Xiasha Sub-district, Qiantang District, Hangzhou 310022, Zhejiang Province, China. yuchenhuan2002@163.com
Research Domain of This Article
Research & Experimental Medicine
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Wei Xie, Xue-Jian Li, Yu-Sen Zhong, Jie Fang, Hua-Zhong Ying, Key Laboratory of Experimental Animal and Safety Evaluation, Hangzhou Medical College, Hangzhou 310013, Zhejiang Province, China
Wei Xie, Xue-Jian Li, Animal Research Center, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310053, Zhejiang Province, China
Hui Qi, Meng Yang, Department of Surgery, University of California, San Diego, CA 92037, United States
Chen-Huan Yu, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
Co-corresponding authors: Hua-Zhong Ying and Chen-Huan Yu.
Author contributions: Ying HZ and Yu CH designed the research study; Xie W, Li XJ, Zhong YS and Fang J performed the research; Zhong YS, Fang J, Yang M and Qi H contributed new reagents and analytic tools; Xie W, Li XJ and Yu CH analyzed the data and wrote the manuscript; All authors have read and approved the final manuscript.
Supported by the Science and Technology Project of the Zhejiang Province, No. 2020Y.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Hangzhou Institute of Medicine, Chinese Academy of Sciences (No. 2023R01102).
Institutional animal care and use committee statement: The experiments were approved by the Animal Ethics Committee of Zhejiang Provincial Laboratory Animal Center (No. 2023R001099).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Chen-Huan Yu, PhD, Dean, Senior Researcher, Hangzhou Institute of Medicine, Chinese Academy of Sciences, No. 150 Dongfang Street, Xiasha Sub-district, Qiantang District, Hangzhou 310022, Zhejiang Province, China. yuchenhuan2002@163.com
Received: April 27, 2025 Revised: June 4, 2025 Accepted: July 14, 2025 Published online: September 15, 2025 Processing time: 142 Days and 18.5 Hours
Abstract
BACKGROUND
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.
AIM
To investigate the antitumor effect of Ginsenoside F4 and mechanism on the maturation of DCs in colorectal cancer (CRC).
METHODS
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.
RESULTS
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.
CONCLUSION
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.
Core Tip: This study provides novel insights into the antitumor effects of natural ginsenoside F4 on the apoptosis of colorectal cancer (CRC) cells by activating the sphingosine-1-phosphate 1-mediated phosphoinositide 3-kinase/protein kinase B and nuclear factor kappa-B pathways in dendritic cells, which subsequently triggers the antitumor effects of cluster of differentiation (CD)8+ T cells. Further investigation revealed that F4 inhibited tumor growth in CRC-bearing mice by recruiting dendritic cells and CD8+ T cells into the tumor immune microenvironment. These findings underscore the promising role of ginsenoside F4 in the management of CRC, highlighting the potential of natural ginsenosides as an adjuvant treatment for this disease.
