Focused Ultrasound Tricks Tumors into Marking Themselves for Destruction

CAR T-cell therapy has transformed the treatment of blood cancers, but its success against solid tumors has been limited. Solid tumors are difficult to target because they are shielded by surrounding tissue and lack consistent surface markers that immune cells can recognize without harming healthy cells. New research now shows that focused ultrasound can reprogram tumor cells themselves, making them visible to immune attack and improving the effectiveness of CAR T-cell therapy.

In the study led by researchers at USC Viterbi School of Engineering (Los Angeles, CA, USA), the team used focused ultrasound waves to mechanically stimulate tumor cells and activate engineered genetic circuits. This approach enables tumor cells to temporarily express a specific immune target, effectively turning them into localized activation sites for immune cells.

The researchers engineered a genetic circuit inside cancer cells that responds to two inputs: mechanical stress from focused ultrasound and exposure to doxycycline, a well-established antibiotic used as a control switch. This dual-key “AND-logic” system ensured gene activation only occurred where and when both signals were present. When activated, the circuit triggered tumor cells to express the protein CD19, a well-known target for CAR T-cells.

Expression of CD19 on a subset of tumor cells acted as a local training signal for CAR T-cells, enabling them to become activated within the tumor microenvironment. Once activated, the CAR T-cells not only destroyed the CD19-marked cells but also attacked neighboring cancer cells. The findings, published in Nature Materials, showed that the approach proved effective even when only 10–15% of tumor cells expressed the priming marker.

Focused ultrasound allows precise, non-invasive targeting deep within the body, limiting immune activation to the tumor site and reducing the risk of off-target toxicity. Although the study focused on prostate cancer models, the platform was also demonstrated in breast cancer and glioblastoma systems. Researchers believe this strategy could significantly expand the use of CAR T-cell therapy to solid tumors and support future applications of ultrasound-controlled cell engineering.

“Doxycycline is already well established in synthetic biology,” said Chi Woo (Nate) Yoon, the study’s first author. “We’re using that well-known system in a new way. The drug acts as a safety switch to open the treatment window, and ultrasound then boosts gene activation exactly where and when we want it.”

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USC Viterbi School of Engineering