DBPR807, a highly selective, safe, and potent CXCR4 antagonist, possesses in vivo efficacy under various HCC settings with supreme benefits on combination therapy, whereby it can significantly synergize with not only antiangiogenic therapy (sorafenib) but also immunotherapy (anti–PD-1) to further extend overall survival. DBPR807 can significantly suppress tumor growth, prevent metastasis, reduce angiogenesis, normalize tumor microenvironment and promote cytotoxic T-cell infiltration. Our results suggest the clinical potential of DBPR807 for the treatment of HCC.