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Objective: Delivery barriers of nanodrug in large tumors due to heterogeneous blood supply, elevated interstitial pressure, and long transport distances can degrade the efficacy of cancer treatment. In this study, we proposed a therapeutic strategy to improve the tumor growth inhibition by injecting pegylated liposomal doxorubicin (PLD), and then applying a short time of ultrasound hyperthermia (HT) on the entire solid tumor, and inflicting ultrasound thermal ablation (Ab) in the low-perfused tumor region. Methods: BALB/c female mice with an average weight of 20 g were adopted and murine breast cancer cells 4T1 were subcutaneously implanted into the flank. A 1.0-MHz planar and a 0.47-MHz focused ultrasound transducers were used, respectively, for the HT and Ab treatment. Results: For a PLD dose of 5 mg/kg, the PLD + HT(42 °C, 10 min) group caused a significant decrease in the tumor size as compared with the control and the PLD group, but there were no significant differences between the PLD + HT group and the PLD + Ab(56 °C, 49 s) + HT group. For a PLD dose of 3 mg/kg, the tumor sizes among the four groups were mutually significant. The level of reduction in tumor was PLD + Ab + HT > PLD + HT > PLD > control. Conclusion: The combination of anticancer nanodrug and ultrasound thermal treatment could remarkably suppress cancer tumor growth with a minimum compromise of side effects. Significance: The strategy of using thermal Ab in locations that are not reached by nanodrug with mild HT shows a promising potential for the entire tumor treatment. [ABSTRACT FROM PUBLISHER]