Theranostics 2021; 11(7):3489-3501. doi:10.7150/thno.54648


Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma

Xiaomeng Dai#, Yixuan Guo#, Yan Hu, Xuanwen Bao, Xudong Zhu, Qihan Fu, Hangyu Zhang, Zhou Tong, Lulu Liu, Yi Zheng, Peng Zhao, Weijia Fang

Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11(7):3489-3501. doi:10.7150/thno.54648. Available from

File import instruction


The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.

Keywords: hepatocellular carcinoma, cancer stem cells, immune evasion, targeting, immunotherapy