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.