Abstract：Focused ultrasound (FUS) can deliver energy noninvasively into tissues deep inside the body and generate local hyperthermia. Chimeric antigen receptor T cell (CAR-T cell) therapy, where T cells are genetically engineered with redirected specificity against malignant cells, has achieved great success in treating hematologic malignancies. However, major challenges remain before CAR-T cell therapy can reach broader applications in solid tumors. For instance, the non-specific targeting of the CAR-T cells against normal tissues (“on-target off-tumor” toxicity) can be a life-threatening side effect. There is hence an urgent need for high-precision control of CAR-T cells to confine their activation at local regions of solid tumors. To this end, we have engineered a class of inducible CAR-T cells that can be acoustogenetically controlled by FUS (FUS-CAR-T cells). We first demonstrated the functionality of the FUS-CAR-T cells in vitro. We then applied the FUS-CAR-T cells in vivo and showed that short-pulsed FUS stimulation activated the engineered T cells at the desired time and location to suppress the growth of subcutaneous tumors. We further demonstrated that the FUS-CAR-T cells significantly reduced the on-target off-tumor toxicity compared with non-inducible CAR-T cells. Our work shows that acoustogenetic control of engineered T cells can facilitate the design of safer cell therapies.