Spatiotemporal control of the bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy

Bacteria-based tumor therapy has recently attracted wide attentions due to its unique capability in targeting tumors and preferentially colonizing the core area of the tumor. Various therapeutic genes were also harbored into these engineering bacteria to enhance their anti-tumor efficacy. However, it is difficult to spatiotemporally control the expression of these inserted genes in the tumor site. Here, we engineered an ultrasound-responsive bacterium (URB) which can induce the expression of exogenous genes in an ultrasound-controllable manner. Owing to the advantage of ultrasound in the tissue penetration, energy focusing into heating, an acoustic remote control of bacterial gene expression can be realized by designing a temperature-actuated genetic switch. Cytokine interferon-γ (IFN-γ), an important immune regulatory molecule that plays a significant role in tumor immunotherapy, was used to test the system. Our results showed a brief hyperthermia by focused ultrasound successfully induced the expression of IFN-γ gene, significantly improving anti-tumor efficacy of URB in vitro and in vivo. Our study provided a novel strategy for bacteria-mediated tumor immunotherapy.