Ultrasound-controllable engineered bacteria for cancer immunotherapy

Rapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutics, including for cancer. Tumor cores often provide niches for systemically administered bacteria to engraft and deliver therapeutic payloads, but off-tumor engraftment can cause harmful effects if payloads are released in healthy tissues. To address this, the authors engineer therapeutic bacteria controllable by focused ultrasound (FUS), a noninvasive modality that selectively heats targeted anatomical sites such as solid tumors. They build a temperature-actuated genetic state switch that produces lasting therapeutic output after brief hyperthermia. Using rational design and high-throughput screening, they optimize switching circuits and link them to the release of immune checkpoint inhibitors. In a mouse cancer model, ultrasound-activated therapeutic microbes are switched on in situ and induce marked tumor growth suppression, enabling spatiotemporal targeting of potent bacterial therapeutics.