Histotripsy for Hepatocellular Carcinoma: From Bench to Bedside

Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, with limited curative options. Histotripsy is a noninvasive focused ultrasound ablation technique that destroys tumors through acoustic cavitation rather than heat-based methods, offering an alternative to radiofrequency and microwave ablation. This review traces histotripsy from preclinical development to U.S. Food and Drug Administration (FDA) approval for liver tumors. Unlike thermal methods, histotripsy creates precise mechanical tissue fractionation while preserving critical structures, including blood vessels and bile ducts. The technology uses short, high-pressure ultrasound pulses to generate cavitation bubble clouds that liquefy targeted tissue without thermal damage. Preclinical studies demonstrated complete tumor ablation with robust immune cell infiltration, suggesting potential abscopal effects. Clinical trials, including THERESA and #HOPE4LIVER, confirmed safety, with #HOPE4LIVER demonstrating short-term efficacy, achieving approximately 95% technical success and approximately 90% 1-year local control rates. Histotripsy received FDA approval in October 2023 for treating liver cancer. The technology shows promise for perivascular lesions where heat-sink effects compromise thermal ablation. Current evidence supports optimal outcomes for tumors 3 cm or smaller, with ongoing research exploring combinations with immunotherapy and applications beyond HCC. Histotripsy represents a paradigm shift in local ablation, offering mechanical precision combined with potential systemic immunostimulatory benefits. © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license.