Enhancing cancer treatment through solid tumor fractionation with nanodroplet-mediated histotripsy and immunotherapy

Checkpoint inhibition holds great promise in enhancing the body's immune response against cancer for durable and widespread anti- tumor effects. However, its efficacy in solid tumor therapy faces challenges such as limited immune cell infiltration and an immunosuppressive tumor microenvironment. This study introduces a cancer therapeutic platform, combining nanodroplet (ND)-mediated low-frequency histotripsy with anti-PD1 (aPD1) checkpoint inhibition. NDs, with their ability to penetrate capillaries and extravasate into tumor tissues, present a promising feature for noninvasive tumor treatments. The proposed method involves a two-step approach for low-energy ND-mediated histotripsy. First, NDs are activated volumetrically using a rotating imaging probe into cavitating gas bubbles. Subsequent low-frequency ultrasound implodes vaporized NDs, inducing tumor fractionation, tissue necrosis, and enhanced immune-cell infiltration, creating a T-cell–inflamed tumor. The goal is to amplify immunotherapy, advancing cancer treatment by targeting both the tumor and its microenvironment. Demonstrated in a breast cancer mouse model, the two-step approach showed significant lesions and tumor debulking. Combining aPD1 checkpoint inhibition further enhanced immune-cell infiltration and reduced tumor growth. Our findings demonstrate the potential of NDs with low-frequency ultrasound and immunotherapy for efficient noninvasive tumor treatment.