Ultrasound-targeted cavitation induced tumor vascular normalization and radiotherapy sensitization in breast cancer

The limited therapeutic efficacy of radiotherapy (RT) in breast cancer is closely linked to hypoxia, which is caused by structurally abnormal vascular networks in the tumor microenvironment (TME). Tumor vascular normalization has emerged as a promising strategy to enhance radiosensitization by alleviating hypoxia. However, current vascular normalization methods face critical limitations, including off-target effects and inadequate spatiotemporal precision. Therefore, developing precise and efficient vascular normalization strategies is crucial for improving RT efficacy. In this study, we developed a tumor vascular normalization strategy based on ultrasound-targeted cavitation for radiosensitization. We synthesized VEGFR2-targeted microbubbles (MB@VEGFR2) to selectively accumulate on tumor vascular endothelial cells. Ultrasound-targeted cavitation enhanced local tumor blood perfusion, increased vascular diameter and maturity, and effectively alleviated hypoxia. By monitoring the time window of vascular normalization and administering RT within this period, tumor growth was significantly suppressed, with a 2.5-fold reduction in tumor volume compared to RT alone. Mechanistically, ultrasound-targeted cavitation promoted ATP release from endothelial cells, activating the PI3K/AKT/eNOS pathway to elevate nitric oxide (NO) production by 4-fold, thereby inhibiting abnormal vascular formation. This study demonstrates that ultrasound-targeted cavitation precisely achieves tumor vascular normalization, effectively improving RT efficacy.