Harnessing the Immune System in Hepatocellular Carcinoma Targeting: Mechanistic Insights and Therapeutic Potential of Natural Products and Traditional Chinese Medicine
Abstract
Liyuan Hao,1 Li Li,2 Yicheng Chen,1 Junxia Gao,3 Yonghui Xie,4 Qiang Li,1 Junlan Lu,1 Zhiqin Zhang11School of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 2Human Resources Department, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 3Experimental Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 4School of Continuing Education, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Zhiqin Zhang, School of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China, Email [email protected]: Hepatocellular carcinoma (HCC) is highly malignant, and most patients are diagnosed at intermediate or advanced stages. Current regimens, including surgery, targeted therapy and immune checkpoint inhibitors (ICIs), are limited by low response rates, drug resistance, prominent toxicities and high costs, so safe and effective combination strategies are urgently needed. Natural products and traditional Chinese medicine (TCM) exert multi-target, multi-pathway and bidirectional immunomodulatory effects, remodel the immunosuppressive tumor microenvironment (TME) of liver cancer, and synergize with immunotherapy, with promising clinical significance as adjuncts to standard treatments. This review systematically summarizes the cellular and non-cellular components of the HCC immune microenvironment and the molecular mechanisms by which natural medicines reverse tumor immune escape and improve immunotherapy sensitivity, covering regulation of immune cells, interference with PD-1/PD-L1, CTLA-4 and TIM-3 pathways, targeting of cancer-associated fibroblasts (CAFs) and the extracellular matrix, modulation of chemokine networks, and inhibition of tumor angiogenesis. Preclinical evidence supporting efficacy enhancement and toxicity reduction upon combination of natural medicines with targeted agents, ICIs, radiotherapy and chemotherapy is also summarized. Current challenges, including tumor heterogeneity, low bioavailability, lack of unified quality standards and insufficient translational evidence, are analyzed, and future directions such as single-cell and spatial multi-omics, nano-delivery systems and gut microbiome analysis are proposed to accelerate mechanism-driven personalized combinations and standardized clinical trials, providing a theoretical basis for the clinical application of natural products and TCM in liver cancer immunotherapy.Keywords: natural products, TCM, liver cancer, immunotherapy, immune microenvironment, immune checkpoint inhibitors, synergistic effects
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BibTeX
@article{hao2026harnessing,
title = {{Harnessing the Immune System in Hepatocellular Carcinoma Targeting: Mechanistic Insights and Therapeutic Potential of Natural Products and Traditional Chinese Medicine}},
author = {Hao L and Li L and Chen Y and Gao J and Xie Y and Li Q and Lu J and Zhang Z},
journal = {Drug Design, Development and Therapy},
year = {2026},
month = nov,
url = {https://www.dovepress.com/harnessing-the-immune-system-in-hepatocellular-carcinoma-targeting-mec-peer-reviewed-fulltext-article-DDDT},
note = {CC BY},
}
RIS
TY - JOUR
TI - Harnessing the Immune System in Hepatocellular Carcinoma Targeting: Mechanistic Insights and Therapeutic Potential of Natural Products and Traditional Chinese Medicine
AU - Hao L
AU - Li L
AU - Chen Y
AU - Gao J
AU - Xie Y
AU - Li Q
AU - Lu J
AU - Zhang Z
PY - 2026
DA - 2026/11/05
JO - Drug Design, Development and Therapy
UR - https://www.dovepress.com/harnessing-the-immune-system-in-hepatocellular-carcinoma-targeting-mec-peer-reviewed-fulltext-article-DDDT
AB - Liyuan Hao,1 Li Li,2 Yicheng Chen,1 Junxia Gao,3 Yonghui Xie,4 Qiang Li,1 Junlan Lu,1 Zhiqin Zhang11School of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 2Human Resources Department, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 3Experimental Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 4School of Continuing Education, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Zhiqin Zhang, School of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China, Email [email protected]: Hepatocellular carcinoma (HCC) is highly malignant, and most patients are diagnosed at intermediate or advanced stages. Current regimens, including surgery, targeted therapy and immune checkpoint inhibitors (ICIs), are limited by low response rates, drug resistance, prominent toxicities and high costs, so safe and effective combination strategies are urgently needed. Natural products and traditional Chinese medicine (TCM) exert multi-target, multi-pathway and bidirectional immunomodulatory effects, remodel the immunosuppressive tumor microenvironment (TME) of liver cancer, and synergize with immunotherapy, with promising clinical significance as adjuncts to standard treatments. This review systematically summarizes the cellular and non-cellular components of the HCC immune microenvironment and the molecular mechanisms by which natural medicines reverse tumor immune escape and improve immunotherapy sensitivity, covering regulation of immune cells, interference with PD-1/PD-L1, CTLA-4 and TIM-3 pathways, targeting of cancer-associated fibroblasts (CAFs) and the extracellular matrix, modulation of chemokine networks, and inhibition of tumor angiogenesis. Preclinical evidence supporting efficacy enhancement and toxicity reduction upon combination of natural medicines with targeted agents, ICIs, radiotherapy and chemotherapy is also summarized. Current challenges, including tumor heterogeneity, low bioavailability, lack of unified quality standards and insufficient translational evidence, are analyzed, and future directions such as single-cell and spatial multi-omics, nano-delivery systems and gut microbiome analysis are proposed to accelerate mechanism-driven personalized combinations and standardized clinical trials, providing a theoretical basis for the clinical application of natural products and TCM in liver cancer immunotherapy.Keywords: natural products, TCM, liver cancer, immunotherapy, immune microenvironment, immune checkpoint inhibitors, synergistic effects
SN - 1177-8881
ER -