This study explores the use of high-intensity focused ultrasound (HIFU)-driven nanomotors for the effective treatment of triple-negative breast cancer (TNBC) by inducing ferroptosis. Through bioinformatics analysis, gambogic acid (GA) is identified as a promising ferroptosis drug, which is loaded into the nanomotors. HIFU not only enhances the accumulation and penetration of nanomotors in tumors but also triggers ferroptosis in TNBC cells. Additionally, HIFU activates ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, leading to significant tumor regression and prevention of metastases. The combination of HIFU-driven nanomotors and immunotherapy shows great potential for treating TNBC.This study explores the use of high-intensity focused ultrasound (HIFU)-driven nanomotors for the effective treatment of triple-negative breast cancer (TNBC) by inducing ferroptosis. Through bioinformatics analysis, gambogic acid (GA) is identified as a promising ferroptosis drug, which is loaded into the nanomotors. HIFU not only enhances the accumulation and penetration of nanomotors in tumors but also triggers ferroptosis in TNBC cells. Additionally, HIFU activates ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, leading to significant tumor regression and prevention of metastases. The combination of HIFU-driven nanomotors and immunotherapy shows great potential for treating TNBC.