CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma

Sheng-Liang Cheng; Chien-Huang Wu; Yun-Jen Tsai; Jen-Shin Song; Hsin-Min Chen; Teng-Kuang Yeh; Chia-Tung Shen; Jou-Chien Chiang; Hsin-Mei Lee; Kuan-Wei Huang; Yuling Chen; J Timothy Qiu; Yu-Ting Yen; Kak-Shan Shia; Yunching Chen

doi:10.1016/j.jconrel.2025.01.066

CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma

J Control Release. 2025 Jan 31:379:967-981. doi: 10.1016/j.jconrel.2025.01.066. Online ahead of print.

Authors

Affiliations

¹ Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan; International Intercollegiate PhD Program, National Tsing Hua University, Hsinchu 30013, Taiwan.
² Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan.
³ Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
⁴ International PhD Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei 11031, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
⁵ Institute of Translational Medicine and New Drug Development, School of Medicine, China Medical University, Taichung, Taiwan. Electronic address: d92449001@ntu.edu.tw.
⁶ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan. Electronic address: ksshia@nhri.edu.tw.
⁷ Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan. Electronic address: yunching@mx.nthu.edu.tw.

PMID: 39863023
DOI: 10.1016/j.jconrel.2025.01.066

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy.

Keywords: CXCL12/CXCR4 axis; Hepatocellular carcinoma; Immunotherapy; PD-1 inhibitor; Tumor-associated macrophage.