The combination of checkpoint blockade with focused ultrasound (FUS)
physical therapy can enhance antitumor immune response by improving the precision and efficiency of
immunotherapy. However, one of the major disadvantages of conventional FUS treatment is the small lesion size, which prolongs
treatment duration. We constructed a focused acoustic vortex (FAV) system with a hollow cylindrical focal region, which exhibited a larger focal region compared to conventional FUS of the same frequency. We developed an all-in-one synergistic
therapy against metastatic
breast cancer based on integrated FAV double combination sequence-regulated phase-transformation nanodroplets (CPDA@PFH) with checkpoint blockade
immunotherapy. A single treatment with FAV + CPDA@PFH resulted in 2.25-fold higher inhibition of
tumor growth compared to that with FUS + CPDA@PFH. In addition, FAV-regulated CPDA@PFH combined with ICB induced a systemic immune response that not only inhibited the growth of primary (98.41% inhibition rate) and distal (80.71%) 4T1
tumors but also reduced the progression of lung
metastasis. In addition, the synergistic
therapy achieved long-term immune memory that effectively prevented
tumor growth and improved the survival time of mice. The long-term survival rate of 4T1
tumor-bearing mice treated with FAV + CPDA@PFH + Anti-PD-L1 was 57.14% on day 60
after treatment. Our study is a proof-of-concept of cascade-amplified synergistic
tumor therapeutics based on ultrasonic-
hyperthermia, cavitation, sonodynamic
therapy (SDT), and checkpoint blockade
immunotherapy through FAV-regulated CPDA@PFH phase-transformation nanodroplets.