Bubble cloud-mediated cavitation for tumor mechanical ablation and effector immune cell deployment

Histotripsy is a cavitation-based tumor ablation technology. To achieve precise cavitation-based ablation requires investigating the cavitation behavior of the bubble cloud and their impact on tumor tissue. This study explored the cavitation behavior of bubble clouds generated by perfluoropentane (PFP)-loaded nanodroplets and efficacy of bubble cloud cavitation in tumor ablation under varying ultrasound intensities. PFP-loaded nanodroplets (∼200 nm) were employed as exogenous cavitation nuclei to reducing the required ultrasound energy for activation of bubble cloud. We investigated the formation, vibration, and collapse of bubble clouds in solution and phantom models under varying ultrasound intensities. Results indicated distinct cavitation patterns: (1) Nanodroplets slowly vaporized and formed continuously vibrating bubble clouds; (2) Nanodroplets rapidly vaporized and resulted in quickly collapsing bubble clouds. At both the cellular and animal levels, cavitation ablation efficacy was examined, revealing that all bubble cloud cavitation patterns could induce immunogenic cell death (ICD), promoting the release of damage-associated molecular patterns (DAMPs) and triggering effector immune cell deployment of peripheral immune response and local tumor infiltration. During the treatment, the ultrasound intensity of 0.5 W/cm² had the highest level of central tumor CD8⁺ T cell infiltration. The conclusion was that sustained bubble cloud oscillation, rather than rapid vaporization and rupture, proved more beneficial for antitumor therapy, particularly in enhancing the local infiltration of effector immune cells.