A high-intensity focused ultrasound (HIFU)-driven nanomotor was developed for effective ferroptosis-immunotherapy of triple-negative breast cancer (TNBC). The nanomotor, composed of PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with gambogic acid (GA) and perfluorooctyl bromide (PFOB), was designed to respond to HIFU for propulsion and on-demand drug release. HIFU not only activated the nanomotors to induce ferroptosis in TNBC cells but also enhanced ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, leading to effective tumor regression and prevention of metastases. Bioinformatics analysis identified GA as a promising ferroptosis inducer, which was loaded into the nanomotors. HIFU-driven nanomotors significantly enhanced tumor accumulation and penetration, and the combination of GA and HIFU treatment significantly reduced tumor viability and induced ferroptosis. The study demonstrated that HIFU not only sensitized TNBC cells to GA but also upregulated ferroptosis-related genes, enhancing the effectiveness of ferroptosis. The nanomotors also promoted the maturation of dendritic cells and the infiltration of T cells, enhancing antitumor immunity. The HIFU-driven nanomotors showed excellent biosafety and therapeutic efficacy in TNBC models, with significant tumor regression and prevention of metastasis. The study highlights the potential of HIFU-driven nanomotors for ferroptosis-immunotherapy of TNBC.A high-intensity focused ultrasound (HIFU)-driven nanomotor was developed for effective ferroptosis-immunotherapy of triple-negative breast cancer (TNBC). The nanomotor, composed of PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with gambogic acid (GA) and perfluorooctyl bromide (PFOB), was designed to respond to HIFU for propulsion and on-demand drug release. HIFU not only activated the nanomotors to induce ferroptosis in TNBC cells but also enhanced ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, leading to effective tumor regression and prevention of metastases. Bioinformatics analysis identified GA as a promising ferroptosis inducer, which was loaded into the nanomotors. HIFU-driven nanomotors significantly enhanced tumor accumulation and penetration, and the combination of GA and HIFU treatment significantly reduced tumor viability and induced ferroptosis. The study demonstrated that HIFU not only sensitized TNBC cells to GA but also upregulated ferroptosis-related genes, enhancing the effectiveness of ferroptosis. The nanomotors also promoted the maturation of dendritic cells and the infiltration of T cells, enhancing antitumor immunity. The HIFU-driven nanomotors showed excellent biosafety and therapeutic efficacy in TNBC models, with significant tumor regression and prevention of metastasis. The study highlights the potential of HIFU-driven nanomotors for ferroptosis-immunotherapy of TNBC.