The activation of immune-stimulatory molecules is critical for effective antitumor immunotherapy. Mechanical high-intensity focused ultrasound (mHIFU) sustains this activation in tumor cell debris through cavitation. To enhance cavitation, perfluorohexane nanodroplets (NDs-PFH) were utilized in this study to lower the cavitation threshold during mHIFU ablation. Our results showed that NDs-PFH combined with mHIFU induced 77.2% Hepa 1-6 tumor cells death, and activated the release of damage-associated molecular patterns (such as HMGB1, CRT, and ATP), enhancing dendritic cell maturation (20.2%) and T cell activation (1.8% of TNF-α+ and 2.7% of IFN-γ+). In vivo, the combination of NDs-PFH and mHIFU effectively suppressed both primary and distant untreated tumors, reducing the tumor volume by 83.3% (from 657.4 mm3 to 110.0 mm3) and metastatic tumor volume by 76.6% (from 365.5 mm3 to 85.6 mm3) through enhanced anticancer immune response and a robust abscopal effect. Furthermore, combining NDs-PFH with mHIFU significantly enhanced the efficacy of immune checkpoint inhibitors in liver cancer. When combined with αPD-1 therapy, tumor inhibition improved by 30% (from 63.6 mm3 to 19.3 mm3) compared to αPD-1 monotherapy. These results highlight the potential of combining mHIFU with a PFH nano-loaded drug delivery system as a promising strategy for advancing antitumor immunotherapy. STATEMENT OF SIGNIFICANCE: Mechanical high-intensity focused ultrasound (mHIFU) can ablate tumors via cavitation effects, however, achieving these effects typically requires an extremely high cavitation threshold. In this study, we utilized widely used perfluorohexane nanodroplets (NDs-PFH) to effectively lower the cavitation threshold. The tumor cell debris generated by the combination of NDs-PFH and mHIFU not only induced immunogenic cells death but also activated antitumor immune responses within the tumor microenvironment. Additionally, our findings demonstrated that this combination elicited a significant abscopal effect and enhanced the efficacy of immunotherapy.Copyright © 2025. Published by Elsevier Inc.