Sound Waves Turn Immune System Into Cancer Fighter

University of Michigan researchers have discovered how histotripsy—a treatment that uses ultrasound waves to destroy liver tumors—transforms the body’s immune system into a cancer-fighting force.

The FDA-approved technology doesn’t just physically destroy cancer cells; it fundamentally changes the tumor environment in ways that help immune cells hunt down cancer throughout the body. This dual action could reshape how doctors approach cancer treatment, offering new hope for patients with advanced disease that has spread beyond a single location.

Beyond Physical Destruction

Since early 2024, University of Michigan Health has been using histotripsy to treat liver tumors following FDA approval in late 2023. The technology works by focusing ultrasound waves to create cavitation bubbles that mechanically destroy tumor tissue without the harsh side effects of chemotherapy or radiation.

But Dr. Anutosh Ganguly and his research team discovered something unexpected happening after treatment. The ultrasound waves weren’t just destroying tumors—they were creating conditions that awakened the patient’s immune system to fight cancer more effectively.

“The relief from hypoxia after histotripsy treatment facilitates a rise in anti-tumor CD8+ T cells that move to the site of the procedure but also to the distant tumors within other parts of the body to oppose their growth,” said Ganguly.

The Oxygen Connection

The key to histotripsy’s immune effects lies in tumor hypoxia—extremely low oxygen levels that create a hostile environment for immune cells. Cancer tumors typically maintain these oxygen-starved conditions as a survival strategy, making it difficult for the body’s natural defenses to penetrate and attack.

Ganguly’s team found that histotripsy treatment rapidly eliminates tumor hypoxia. When oxygen levels return to normal, it triggers a cascade of changes that transform the tumor from an immune-suppressed environment into one where cancer-fighting cells can thrive.

The research, published in Molecular Cancer Therapeutics, focused on melanoma models but has implications for other cancer types including pancreatic cancer. What makes this discovery particularly exciting is that the immune activation affects not just the treated tumor, but cancer cells throughout the body.

How the Immune Awakening Works

The research revealed a sophisticated biological mechanism behind histotripsy’s immune effects:

• Hypoxia elimination: Ultrasound waves restore normal oxygen levels in tumors
• HIF1α suppression: Reduced hypoxia shuts down survival proteins that help cancer cells evade immune detection
• CXCL10 upregulation: The tumor begins producing signals that attract immune cells
• CD8+ T cell infiltration: Cancer-fighting immune cells flood the tumor site and travel to distant cancer locations

The CXCR3 Pathway Discovery

One of the most significant findings that extends beyond previous observations involves the CXCR3-CXCL10 signaling pathway. The research team discovered that histotripsy triggers increased production of CXCL10, a chemical signal that acts like a beacon for CXCR3-positive CD8+ T cells.

When researchers blocked this pathway using anti-CXCR3 antibodies, the therapeutic benefits of histotripsy were significantly reduced. This suggests that the CXCR3-CXCL10 interaction is essential for the treatment’s immune-stimulating effects—a mechanistic detail that could guide future treatment protocols.

The team also found that CD8-deficient mice showed dramatically reduced benefits from histotripsy, confirming that these specific immune cells are crucial for the treatment’s systemic anti-cancer effects.

Timing and Durability Challenges

The research revealed important limitations that could inform treatment strategies. The immune-stimulating effects of histotripsy are temporary—hypoxia levels and tumor growth inhibition eventually return as CD8+ T cell infiltration diminishes over time.

This finding suggests that the timing of additional treatments could be crucial. The window when tumors are most vulnerable to immune attack appears to be limited, potentially requiring carefully scheduled combination therapies to maximize benefits.

Combination Therapy Potential

“So, in addition to physically destroying tumor cells, histotripsy stimulates the patient’s own immune system to fight cancer more effectively throughout the body,” said Ganguly.

The research team tested this concept by combining histotripsy with trametinib, a MEK inhibitor that suppresses HIF1α. This combination substantially enhanced the therapeutic effects compared to histotripsy alone, demonstrating how understanding the underlying mechanisms can lead to improved treatment protocols.

“The additional effect of activating the patient’s own immune system against cancer cells by histotripsy can help the patient’s body respond better to other types of cancer treatment they may be receiving in addition to the histotripsy such as radiation and chemotherapy,” said Ganguly.

Expanding Applications

While histotripsy is currently approved only for liver tumors, this research opens doors for treating other cancer types. The ability to simultaneously destroy tumors and activate systemic immune responses could be particularly valuable for patients with metastatic disease.

The technology is already expanding across Michigan and surrounding states. As more centers adopt histotripsy, researchers will have additional opportunities to study its immune effects in diverse patient populations and cancer types.

Future Research Directions

Ganguly and his team are continuing to investigate how histotripsy affects the entire body’s response to cancer. Their work focuses on identifying which additional therapies can best enhance histotripsy’s effects and determining optimal timing for combination treatments.

The research has particular implications for immunotherapy approaches. Understanding how mechanical tumor destruction can prime the immune system could lead to new strategies for combining focused ultrasound with immune checkpoint inhibitors or other immunotherapeutic agents.

“Our work to continue understanding the ways that histotripsy impacts the whole body can open doors for new and potentially more effective ways to treat cancer that have less patient side effects,” said Ganguly.

As histotripsy technology continues to evolve, this research provides a scientific foundation for maximizing its therapeutic potential beyond simple tumor destruction, transforming it into a tool that can orchestrate the body’s own defenses against cancer.