Research Paper Volume 13, Issue 2 pp 2912—2940

Systems pharmacology dissection of Epimedium targeting tumor microenvironment to enhance cytotoxic T lymphocyte responses in lung cancer

Chao Huang1, *, , Zhihua Li2, *, , Jinglin Zhu2, , Xuetong Chen1, , Yuanyuan Hao2, , Ruijie Yang2, , Ruifei Huang2, , Jun Zhou3, , Zhenzhong Wang3, , Wei Xiao3, , Chunli Zheng2, , Yonghua Wang1,2, ,

  • 1 Bioinformatics Center, College of Life Sciences, Northwest A&F University, Yangling 712100, Shaanxi, China
  • 2 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an 710069, China
  • 3 State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical, Co., Ltd., Lianyungang 222001, China
* Equal contribution

Received: April 15, 2020       Accepted: October 1, 2020       Published: January 17, 2021
How to Cite

Copyright: © 2021 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The clinical notably success of immunotherapy fosters an enthusiasm in developing drugs by enhancing antitumor immunity in the tumor microenvironment (TME). Epimedium, is a promising herbal medicine for tumor immunotherapy due to the pharmacological actions in immunological function modulation and antitumor. Here, we developed a novel systems pharmacology strategy to explore the polypharmacology mechanism of Epimedium involving in targeting TME of non-small cell lung cancer (NSCLC). This strategy integrates the active compounds screening, target predicting, network pharmacology analysis and onco-immune interacting to predict the potential active compounds that trigger the antitumor immunity. Icaritin (ICT), a major active ingredient of Epimedium, was predicted to have good drug-like properties and target immune microenvironment in NSCLC via regulating multiple targets and pathways. Then, we evidenced that the ICT effectively inhibited tumor growth in LLC tumor-bearing mice and increases the infiltration of CD8+ T cells in TME. In addition, we demonstrated that ICT promotes infiltration of CD8+ T cells in TME by downregulating the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulating chemotaxis (CXCL9 and CXCL10). Overall, the systems pharmacology strategy offers an important paradigm to understand the mechanism of polypharmacology of natural products targeting TME.


NSCLC: non-small-cell lung cancer; TME: tumor microenvironment; ICT: icaritin; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database; OB: Oral bioavailability; DL: Drug-likeness; HF: Half-life; SEA: similarity ensemble approach; WES: weighted ensemble similarity; SysDT: algorithm and systematic drug targeting tool; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; DEGs: differentially expressed genes; LLC: Lewis lung carcinoma; ADME: Absorption, Distribution, Metabolism, and Excretion.