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CXCR4 Antagonist-Loaded Nanoparticles Reprogram the Tumor Microenvironment and Enhance Immunotherapy in Hepatocellular Carcinoma

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE276234 | GEO | 2025/08/07

REPOSITORIES: GEO

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Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014). Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

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CXCR4 Antagonist-Loaded Nanoparticles Reprogram the Tumor Microenvironment and Enhance Immunotherapy in Hepatocellular Carcinoma

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