The treatment of tumors with focused ultrasound can stimulate the immune system and potentially enhance the body’s ability to manage cancer.

Courtesy of the National Cancer Institute

When a tumor is ablated, the exposed proteins and cellular debris can act as antigens that may trigger an increased immune response to the tumor, both locally and at distant metastases. Furthermore, thermal ablation may cause local inflammation, stimulate the recruitment of immune effector cells, and activate anti-tumor adaptive immunity, all of which can increase the body’s ability to fight cancer.

Immunomodulation through focused ultrasound could noninvasively augment and enhance existing chemotherapy and immunotherapy treatments for the management of tumors. Several different ultrasound modalities, including thermal ablation, mechanical ablation (histotripsy), and mild hyperthermia, have been shown to trigger an immune response in the body by releasing antigens and danger signals from cancer cells. The effect of the focused ultrasound treatment appears to depend on the ultrasound modality used and the type of tumor being treated.

There are several proposed methods by which focused ultrasound may induce an immunotherapeutic response. Focused ultrasound treatments may stress or damage tumor cells, causing the release of danger-associated molecular patterns (DAMPs) such as heat shock proteins (HSP60 and 70), calreticulin, and ATP, which activate the innate immune system, increase the immunogenicity of the tumor, and improve immune cell trafficking to the tumor. Focused ultrasound may also mitigate tumor-induced immunosuppression by decreasing levels of immunosuppressive cytokines (e.g., VEGF, TGF-ß1, and TGF-ß2). Cancer cell destruction creates tumor debris that act as antigens for antigen presenting cells, enhancing both the innate and adaptive immune response. Lower power focused ultrasound treatments can disrupt the extracellular matrix and make it easier for immune cells to infiltrate the tumor, particularly when there is dense stroma (e.g., pancreatic cancer).

Despite their promise, these effects may not be strong enough to control tumor growth on their own. Researchers are investigating the use of focused ultrasound in combination with other cancer treatments such as immunotherapeutics and CAR-T cells. Because of focused ultrasound’s ability to penetrate the blood brain barrier and other dense stroma, it is an attractive modality to potentially boost the delivery and effectiveness of immunotherapies in notoriously difficult to treat cancers. Additionally, research into immunotherapies has shown that they are more successful in patients who have a baseline immune response to the cancer, which focused ultrasound may be poised to provide.

The Focused Ultrasound Foundation has identified a list of burning questions regarding the use of focused ultrasound in immunooncology that need to be answered to move the field forward. The Foundation relies on these burning questions to determine funding priorities and other efforts.

Burning Questions
  1. What are the comparative immune effects – i.e., signaling pathways/molecules – induced by different focused ultrasound modes? How do these compare to other therapies, such as radiation, cryoablation, RF ablation?
  2. How do the immune effects of focused ultrasound vary by tumor type?
  3. What clinical disease targets are ideal for focused ultrasound plus immunotherapy combinations?
  4. How can we optimize focused ultrasound treatments for immunomodulation (i.e., drugs combinations, partial vs. total tumor treatment, timing of treatments)?
  5. What metrics can be used to predict clinical success (Tcell ratios,etc)? Can blood samples in the absence of biopsies reliably predict response?

Novel Advances in Breast Cancer Treatment with David Brenin, MD | University of Virginia School of Medicine, Gregory Czarnota, MD, PhD | Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Ying Meng, MD | University of Toronto, Natasha Sheybani, PhD | University of Virginia

Fireside Chat: Focused Ultrasound for Cancer Immunotherapy with Jill O’Donnell-Tormey, PhD | Cancer Research Institute, Theresa LaVallee, PhD | Parker Institute for Cancer Immunotherapy, Jessica Foley, PhD | Focused Ultrasound Foundation

Immunotherapy for Brain Tumors by Michael Lim, MD | Johns Hopkins University

Suggested reading

Hiniker S, Chen D, Knox S. Abscopal Effect in a Patient with Melanoma. N. Engl. J. Med. 2012;366:2035–6.

Joiner JB, Pylayeva-Gupta Y, Dayton PA. Focused Ultrasound for Immunomodulation of the Tumor Microenvironment. Journal of immunology (Baltimore, Md : 1950). 2020;205(9):2327-2341. doi:10.4049/jimmunol.1901430

Ho YJ, Li JP, Fan CH, Liu HL, Yeh CK. Ultrasound in tumor immunotherapy: Current status and future developments. Journal of controlled release : official journal of the Controlled Release Society. 2020;323:12-23. doi:10.1016/j.jconrel.2020.04.023

Shi G, Zhong M, Ye F, Zhang X. Low-frequency HIFU induced cancer immunotherapy: tempting challenges and potential opportunities. Cancer biology & medicine. 2019;16(4):714-728. doi:10.20892/j.issn.2095-3941.2019.0232

Sheybani ND, Price RJ. Perspectives on Recent Progress in Focused Ultrasound Immunotherapy. Theranostics. 2019;9(25):7749-7758. doi:10.7150/thno.37131

Mauri G, Nicosia L, Xu Z, et al. Focused ultrasound: tumour ablation and its potential to enhance immunological therapy to cancer. The British Journal of Radiology. 2018;91(1083):20170641. doi:10.1259/bjr.20170641

van den Bijgaart RJE, Eikelenboom DC, Hoogenboom M, et al. Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies. Cancer immunology, immunotherapy : CII. 2017;66(2):247-258. doi:10.1007/s00262-016-1891-9

Maloney E, Khokhlova T, Pillarisetty VG, et al. Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy. International reviews of immunology. Published online September 2017:1-14. doi:10.1080/08830185.2017.1363199

Curley CT, Sheybani ND, Bullock TN, Price RJ. Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities. Theranostics. 2017;7(15):3608-3623. doi:10.7150/thno.21225

Cirincione R, Di Maggio FM, Forte GI, et al. High-Intensity Focused Ultrasound– and Radiation Therapy–Induced Immuno-Modulation: Comparison and Potential Opportunities. Ultrasound in Medicine & Biology. 2017;43(2):398-411. doi:10.1016/j.ultrasmedbio.2016.09.020

Cohen-Inbar O, Xu Z, Sheehan JP. Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept. Journal of therapeutic ultrasound. 2016;4(1):2. doi:10.1186/s40349-016-0046-y

Bastianpillai C, Petrides N, Shah T, Guillaumier S, Ahmed HU, Arya M. Harnessing the immunomodulatory effect of thermal and non-thermal ablative therapies for cancer treatment. Tumor Biology. 2015;36(12):9137-9146. doi:10.1007/s13277-015-4126-3

Zhou Y. High-Intensity Focused Ultrasound Treatment for Advanced Pancreatic Cancer. Gastroenterology Research and Practice. 2014;2014:1-11. doi:10.1155/2014/205325

Wu F, Wang ZB, Lu P, et al. Activated anti-tumor immunity in cancer patients after high intensity focused ultrasound ablation. Ultrasound in medicine & biology. 2004;30(9):1217-1222. doi:10.1016/j.ultrasmedbio.2004.08.003

Kim, Chulyong, Michael Lim, Graeme F. Woodworth, and Costas D. Arvanitis. The Roles of Thermal and Mechanical Stress in Focused Ultrasound-Mediated Immunomodulation and Immunotherapy for Central Nervous System Tumors. Journal of Neuro-Oncology 157 (2): 221–36. 2022.

Hendricks-Wenger, Alissa, Lauren Arnold, Jessica Gannon, Alex Simon, Neha Singh, Hannah Sheppard, Margaret A. Nagai-Singer, et al. Histotripsy Ablation in Preclinical Animal Models of Cancer and Spontaneous Tumors in Veterinary Patients: A Review. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control 69 (1): 5–26. 2022.

Hendricks-Wenger, Alissa, Ruby Hutchison, Eli Vlaisavljevich, and Irving Coy Allen. Immunological Effects of Histotripsy for Cancer Therapy. Frontiers in Oncology 11 (May): 681629. 2021.

Sabbagh, Aria, Kevin Beccaria, Xiaoyang Ling, Anantha Marisetty, Martina Ott, Hillary Caruso, Emily Barton, et al. 2021. Opening of the Blood–Brain Barrier Using Low-Intensity Pulsed Ultrasound Enhances Responses to Immunotherapy in Preclinical Glioma Models. Clinical Cancer Research 27 (15): 4325–37. 2021.

Eranki, Avinash, Priya Srinivasan, Mario Ries, AeRang Kim, Christopher A Lazarski, Christopher T Rossi, Tatiana D Khokhlova, et al. High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 26 (5): 1152–61. 2020.

Vidal-Jove, Joan, Xavier Serres-Creixams, Timothy J. Ziemlewicz, and Jonathan M. Cannata. Liver Histotripsy Mediated Abscopal Effect—Case Report. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control 68 (9): 3001–5. 2021.

Click here for additional references from PubMed.