BACKGROUND: Sono-photodynamic therapy (SPDT), the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT), is a promising tumor treatment method. However, the hypoxic tumor microenvironment greatly compromises the efficacy of SPDT. Pyroptosis, a new type of programmed cell death, is mainly induced by some chemotherapeutic drugs in the current research, and rarely by SPDT. RNA sequencing (RNA-seq) is a high-throughput sequencing technique that comprehensively profiles the transcriptome, revealing the full spectrum of RNA molecules in a cell. Here, we constructed IR780@O nanobubbles (NBs) with photoacoustic dual response and hypoxia improvement properties to fight triple negative breast cancer (TNBC), and demonstrated that SPDT could kill TNBC cells through pyroptosis pathway. RNA-seq further revealed potential mechanisms and related differentially expressed genes. METHODS: Thin-film hydration and mechanical vibration method were utilized to synthesize IR780@O NBs. Subsequently, we characterized IR780@O NBs and examined the cytotoxicity as well as ROS production ability. A series of experiments were conducted to verify that SPDT killed TNBC cells through pyroptosis. RESULTS: IR780@O NBs were successfully prepared and had certain stability. Compared with SDT alone, SPDT increased therapeutic effect by 1.67 times by generating more ROS, and the introduction of NBs and O NBs (2.23 times and 2.93 times compared with SDT alone) could further promote this process. Other experiments proved that TNBC cells died by pyroptosis pathway. Moreover, the in-depth mechanism revealed that colony stimulating factor (CSF) and C-X-C motif chemokine ligand (CXCL) could be potential targets for the occurrence of pyroptosis in TNBC cells. CONCLUSION: The IR780@O NBs prepared in this study increased the degree of TNBC cell pyroptosis through SPDT effect and alleviation of hypoxia, and cellular senescence might be a biological process closely related to pyroptosis in TNBC.