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Metastasis is the main cause of cancer treatment failure and death. However, current therapies are designed to impair carcinoma metastasis mainly by impairing initial dissemination events. CXCR4 is a G-protein coupled receptor that exclusively binds its ligand CXCL12, which can stimulate cells to metastasize to distant sites. As the antagonist of chemokine receptor CXCR4, Peptide S exhibited anti-metastasis effect. In order to enhance treatment efficiency through destroying primary tumors and inhibiting their metastases, we combined PEGylated doxorubicin-loaded liposomes (DOX-Lip) with anti-metastasis Peptide S for tumor therapy for the first time. DOX-Lip exhibited similar cytotoxic activity compared to free DOX in vitro, and Peptide S showed no toxic effect on cell viability. However, the Peptide S sensitized CXCR4-positive B16F10 melanoma cells to DOX-Lip (5 μM) when cocultured with stromal cells (50.18 ± 0.29% of viable cells in the absence of Peptide S vs 33.70 ± 3.99% of viable cells in the presence of Peptide S). Both Peptide S and DOX-Lip inhibited the adhesion of B16F10 cells to stromal cells. We further confirmed that the inhibition of phosphorylated Akt (pAkt) by Peptide S played a key role due to the fact that activation of pAkt by DOX-Lip promoted resistance to chemotherapy. Migration and invasion assays showed that DOX-Lip enhanced anti-metastasis effect of Peptide S in vitro because of the cytotoxicity of doxorubicin. In vivo studies also showed that the combined treatment with DOX-Lip and Peptide S not only retarded primary tumor growth, but also reduced lung metastasis. Both the DOX-Lip and DOX-Lip + Peptide S exhibited even more outstanding tumor inhibition effect (with tumor growth inhibition rates of 32.1% and 37.9% respectively). In conclusion, our combined treatment with CXCR4 antagonist and liposomal doxorubicin was proved to be promising for antitumor and anti-metastasis therapy.