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Ultrasound for Cancer Therapy
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Ultrasound for Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 November 2026 | Viewed by 5167

Editors

Dr. Zhen Xu

E-Mail Website
Guest Editor
1. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
2. Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA
3. Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA
Interests: histotripsy; ultrasound therapy
Dr. Natasha D. Sheybani

E-Mail Website
Guest Editor
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USA
Interests: ultrasound therapy; immunotherapy; theranostics

Special Issue Information

Dear Colleagues,

Ultrasound has rapidly gained clinical traction as a technique for non-invasive cancer therapy, ranging from high intensity focused ultrasound (HIFU) thermal ablation of essential tremor and prostate tumors to histotripsy treatment of primary and metastatic liver tumors and blood–brain barrier opening to augment the delivery of therapeutics to brain tumors. Globally, there are now hundreds of clinical trials investigating ultrasound cancer therapy, including applications in brain, pancreatic, renal, breast, and other cancers.

This burgeoning clinical landscape is supported by a vibrant and rapidly expanding body of pre-clinical research that is establishing and mechanistically investigating various ultrasound therapy techniques (e.g., HIFU, histotripsy, enhanced drug delivery, enhanced immunotherapy, sonodynamic therapy, blood–brain barrier opening, and sonobiopsy). There is mounting evidence that ultrasound can be effective in the treatment of many cancer types.

Thus, the main objective of this Special Issue, “Ultrasound for Cancer Therapy”, is to showcase the latest pre-clinical and clinical research findings advancing ultrasound as a non-invasive tool for cancer treatment.

Dr. Zhen Xu
Dr. Natasha D. Sheybani
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HIFU
  • histotripsy
  • drug delivery
  • immunotherapy
  • sonodynamic therapy
  • blood brain barrier opening
  • sonobiopsy
  • cancer treatment
  • image-guided therapy

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Published Papers (5 papers)

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Research

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23 pages, 17021 KB  
Article
Immunological and Clinical Outcomes Associated with Histotripsy Ablation in Spontaneously Occurring Canine Osteosarcoma; Veterinary Clinical Trial Results
by Alayna. N. Hay, Lauren Ruger, Elliana R. Vickers, Sheryl Coutermarsh-Ott, Eli Vlaisavljevich and Joanne Tuohy
Cancers 2026, 18(15), 2511; https://doi.org/10.3390/cancers18152511 - 5 Aug 2026
Viewed by 428
Abstract
Background: Osteosarcoma (OS) is a devasting bone cancer that occurs primarily in pediatric patients, and pet dogs, and treatment options have not advanced in decades. There is a profound need for advancement of treatment options to improve patient prognosis given the grim 70% [...] Read more.
Background: Osteosarcoma (OS) is a devasting bone cancer that occurs primarily in pediatric patients, and pet dogs, and treatment options have not advanced in decades. There is a profound need for advancement of treatment options to improve patient prognosis given the grim 70% 5-year survival rate for human patients, and 10–12-month median survival for canine patients. A major hurdle in advancing treatment options is overcoming the immunosuppressive tumor microenvironment to mitigate metastatic disease progression—the leading cause of mortality in OS patients. Methods: We investigated the ability of a mechanical focused ultrasound ablation modality, histotripsy, to induce acute immunomodulation in canine patients with spontaneously occurring OS. Results: Immunomodulation was evident locally and systemically. Tumor gene signatures indicated upregulation of pro-inflammatory signaling pathways and T-cell receptor signaling, and B-cell activation, and systemically, increased monocyte activation was observed within 5 days post-histotripsy ablation. A subset of patients who received histotripsy prior to definitive standard-of-care exceeded the reported expected median survival time of 10–12 months for canine OS patients that received definitive standard-of-care only. Conclusions: Our results demonstrate the promising potential of histotripsy to overcome the immunosuppressive tumor microenvironment. Full article
(This article belongs to the Special Issue Ultrasound for Cancer Therapy)
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17 pages, 3605 KB  
Article
Safe and Effective Histotripsy Ablation of Human Liver Tumors in a Genetically Modified Porcine Model
by Tamalika Paul, Jessica Gannon, Manali Powar, Cora Youngs, Cassandra S. Poole, Carley M. Elliott, Mackenzie K. Woolls, Khan Imran Mohammad, Sherrie Clark-Deener, Christopher Byron, Michael Edwards, Sheryl Coutermarsh-Ott, Kristin Eden, Kiho Lee, Timothy J. Ziemlewicz, Eli Vlaisavljevich and Irving C. Allen
Cancers 2026, 18(15), 2432; https://doi.org/10.3390/cancers18152432 - 29 Jul 2026
Viewed by 480
Abstract
Background: Liver cancers are a major cause of morbidity and mortality in patients where effective, non-invasive treatment options remain limited. Objective: Histotripsy is a non-invasive, non-thermal, image-guided focused ultrasound method of ablation that mechanically disrupts cells and offers a range of potential advantages [...] Read more.
Background: Liver cancers are a major cause of morbidity and mortality in patients where effective, non-invasive treatment options remain limited. Objective: Histotripsy is a non-invasive, non-thermal, image-guided focused ultrasound method of ablation that mechanically disrupts cells and offers a range of potential advantages over other ablation modalities. The lack of physiologically and anatomically relevant animal models of human liver cancer has significantly hindered biomedical device development, including histotripsy. Methods: To address these limitations, we developed a clinically relevant large animal orthotopic, dual-tumor model of human liver cancer and utilized these unique animals to evaluate the safety and efficacy of histotripsy. Here, we utilized immunocompromised pigs with genetic modifications in their IL-2RG and RAG2 genes and orthotopically engrafted human hepatocellular carcinoma (HepG2/C3A) and pancreatic adenocarcinoma (Panc-1) cells within the liver. The models were designed to recapitulate primary and metastatic liver tumor phenotypes. Results: Histotripsy enabled real-time visualization of the treatment by the formation of bubble clouds and accurate targeting of the lesions. Histological analysis confirmed the engraftment of tumor cells and the ablation of targeted tissue. Serum biomarkers demonstrated no significant differences in bilirubin, ALT, ALKP, or CK post-treatment, suggesting that histotripsy treatment was well tolerated with minimal hepatic dysfunction or hepatocellular injury. Conclusions: These findings establish a novel, clinically relevant porcine model of primary and metastatic liver tumors and demonstrate the safety and feasibility of using this model for evaluating histotripsy as a noninvasive modality for precise tumor ablation. Full article
(This article belongs to the Special Issue Ultrasound for Cancer Therapy)
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22 pages, 6329 KB  
Article
Histotripsy-Initiated Immune Response Synergizes with Chemotherapy in a Neuroblastoma Murine Model
by Natalia Antonides-Jensen, Muskan Singh, Yuqing Xue, Fernando Flores-Guzman, Lydia L. Wu, Samantha S. Yee, Jacky Gomez-Villa, Timothy L. Hall, Mark A. Applebaum, Kenneth B. Bader and Sonia L. Hernandez
Cancers 2026, 18(8), 1249; https://doi.org/10.3390/cancers18081249 - 15 Apr 2026
Viewed by 1136
Abstract
Background: High-risk neuroblastoma (NB) is a pediatric malignancy associated with metastases and an immunosuppressive tumor microenvironment. Standard-of-care treatments like chemotherapy are often ineffective, which motivates the investigation of adjuvant approaches. Histotripsy is a noninvasive focused ultrasound therapy that ablates tissue through the mechanical [...] Read more.
Background: High-risk neuroblastoma (NB) is a pediatric malignancy associated with metastases and an immunosuppressive tumor microenvironment. Standard-of-care treatments like chemotherapy are often ineffective, which motivates the investigation of adjuvant approaches. Histotripsy is a noninvasive focused ultrasound therapy that ablates tissue through the mechanical action of bubble clouds. In addition to disruption of the targeted tumor, non-targeted lesions may exhibit growth delay after the histotripsy procedure. The primary hypothesis of this study was histotripsy-induced shifts in the tumor microenvironment will improve the response of metastatic NB to chemotherapy. Methods: Female A/J mice flanks were inoculated bilaterally with 1 × 106 Neuro-2a cells. Histotripsy was applied to one tumor (200–500 mm3), with or without concurrent administration of liposomal doxorubicin (LDOX). The contralateral tumor served as a model of non-targeted distal metastases. Following treatment, tumors were monitored indefinitely for growth, or assessed after 5–7 days with flow cytometry, single-cell RNA sequencing, and immunohistochemistry. Results: Histotripsy alone delayed the growth of treated and contralateral tumors relative to controls (p = 0.01 and p < 0.0001, respectively) and increased CD8+ T and CD11b+ cells (p < 0.05 for both comparisons). Further, NB cells in targeted and contralateral tumors exhibited a decrease in c-Myc expression and cell-cycle activity, and upregulation of interferon and apoptosis pathways. Histotripsy combined with LDOX had the longest delay in tumor growth (p < 0.0001 vs. untreated controls; p < 0.001 vs. other arms) and greatest expression of CD8+ and MOMA staining. Conclusions: These findings indicate that histotripsy induces a systemic antitumor immune response that potentiates chemotherapy efficacy in this model of metastatic NB. Full article
(This article belongs to the Special Issue Ultrasound for Cancer Therapy)
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15 pages, 3094 KB  
Article
First Report of Histotripsy-Induced Survival Benefit in Murine Glioblastomas
by Sarah Duclos, Tarana Parvez Kaovasia, Adam Fox, Ashley Cornett, Aditya S. Pandey and Zhen Xu
Cancers 2026, 18(4), 622; https://doi.org/10.3390/cancers18040622 - 13 Feb 2026
Viewed by 1939
Abstract
Background: Glioblastoma (GBM) is a lethal, highly invasive, and recurrent brain tumor. Standard treatment combines maximal surgical resection, radiation, and chemotherapy; however, such approaches are often infeasible for tumors in eloquent brain regions. Objective: Histotripsy is a noninvasive, nonthermal ultrasound-based mechanical ablation modality [...] Read more.
Background: Glioblastoma (GBM) is a lethal, highly invasive, and recurrent brain tumor. Standard treatment combines maximal surgical resection, radiation, and chemotherapy; however, such approaches are often infeasible for tumors in eloquent brain regions. Objective: Histotripsy is a noninvasive, nonthermal ultrasound-based mechanical ablation modality that employs focused acoustic energy for targeted tissue destruction. This study aimed to investigate the feasibility, safety, and therapeutic effect of a one-time transcranial histotripsy treatment in a pre-clinical murine GBM model. Methods: GL261 GBM cells were orthotopically implanted into C56BL/6 mouse brains. Transcranial histotripsy was performed using a stereotactically guided 2 MHz transducer targeting either lower (25%) or higher (75%) tumor volume, with 5 or 10 pulses per location (PPL) administered. Tumor growth and cerebral injury were monitored with weekly magnetic resonance imaging (MRI) following treatment. At the study endpoint, hematoxylin and eosin (H&E) histology assessed residual tumor burden and histotripsy-induced tissue changes. Results: Mice receiving 5 PPL high-percent treatment (>30 sites) showed a statistically significant median survival extension of 5 days (18.5%) compared to untreated controls. MRI demonstrated marked tumor volume reduction in the high-percent treatment group at week 4, while H&E confirmed increased tumor necrosis and cellular damage in the treated cohort. Conclusions: Single-session, incisionless transcranial histotripsy was well tolerated and conferred mild yet meaningful survival advantages in this GBM model. These results support ongoing exploration of histotripsy, alone or in combination with existing therapies, for safe and effective treatment of challenging brain tumors. Full article
(This article belongs to the Special Issue Ultrasound for Cancer Therapy)
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Review

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25 pages, 1047 KB  
Review
Beyond Ablation: A Review of Immune Responses Across Focused Ultrasound Modalities
by Carley M. Elliott, Tamalika Paul, Michaela Hall, Sofia Killar, Eli Vlaisavljevich and Irving C. Allen
Cancers 2026, 18(15), 2460; https://doi.org/10.3390/cancers18152460 - 31 Jul 2026
Viewed by 493
Abstract
Focused ultrasound (FUS) comprises a diverse group of non-invasive, non-ionizing acoustic technologies that have evolved from tools for localized tissue destruction into platforms capable of influencing complex biological processes. In oncology, growing evidence suggests that the effects of focused ultrasound extend beyond direct [...] Read more.
Focused ultrasound (FUS) comprises a diverse group of non-invasive, non-ionizing acoustic technologies that have evolved from tools for localized tissue destruction into platforms capable of influencing complex biological processes. In oncology, growing evidence suggests that the effects of focused ultrasound extend beyond direct tumor treatment to include modulation of the tumor microenvironment and anti-tumor immunity. This review examines the major FUS modalities currently under investigation for cancer therapy, including high-intensity focused ultrasound (HIFU), intrinsic threshold histotripsy, boiling histotripsy, shock-scattering histotripsy, and low-intensity focused ultrasound (LIFU), with emphasis on the distinct physical mechanisms that underlie their biological effects. Although these modalities differ in how they interact with tissue, they share the capacity to alter tumor biology through changes in antigen availability, inflammatory signaling, and immune cell activity. These responses have been associated with enhanced immune recognition of tumors, remodeling of immunosuppressive microenvironments, and improved therapeutic responsiveness in preclinical and emerging clinical studies. As interest in focused ultrasound continues to expand, understanding the relationship between modality-specific bioeffects and downstream immune outcomes has become increasingly important. Collectively, the literature highlights focused ultrasound as a versatile therapeutic platform capable of linking precise local intervention with broader biological and immunological consequences, supporting its continued development as both a tumor-directed and immune-modulating strategy in cancer therapy. Full article
(This article belongs to the Special Issue Ultrasound for Cancer Therapy)
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