CXCR4 Antagonist-Loaded Nanoparticles Reprogram the Tumor Microenvironment and Enhance Immunotherapy in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a leading cause of cancer death, with limited treatment options for advanced stages. Although PD-1 inhibitors like nivolumab and pembrolizumab are approved for advanced HCC, their effectiveness is often hampered by the immunosuppressive tumor microenvironment, driven by hypoxia-driven CXCL12/CXCR4 axis activation. Herein, we develop 807-NP, a lipid-coated tannic acid nanoparticle to encapsulate and deliver BPRCX807, a potent antagonist of CXCR4, into HCC tumors. 807-NP enhances pharmacokinetics and improves tumor availability of BPRCX807 without systemic toxicity. Our findings show that 807-NP blocks the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages, promoting their repolarization to an anti-tumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NP significantly remodels the immunosuppressive tumor microenvironment by reprogramming tumor associated macrophages (TAMs) towards an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. This suppresses primary tumor growth and metastasis while enhancing the efficacy of cancer immunotherapies, including PD-1 blockades and whole cancer cell vaccines, by facilitating T cell activation. Our work demonstrates the potential of nanotechnology-enabled delivery of CXCR4 antagonists to improve cancer immunotherapy. Overall design: Comparative gene expression profiling analysis of RNA-seq data for murine HCC tumors with or without treatment of nanoparticle loaded with CXCR4 inhibitor BPRCX807.