Although ultrasound therapy is efficacious and safe in clinical oncology, its capacity to elicit an anti-tumor immune response is constrained by ultrasound-induced apoptosis. Pyroptosis, which releases immunogenic damage-associated molecular patterns (DAMPs), can significantly enhance immune activation. It necessitates robust Gasdermin E (GSDME) expression in cancer cells for caspase-3-mediated pyroptosis. An epigenetic strategy is introduced to induce cancer pyroptosis during sonotherapy using a nanocoordinator (HTA) constructed through metal-phenolic coordination involving Aza (a DNA methyltransferase inhibitor), TiO₂ nanoparticles, and polyphenol-modified hyaluronic acid. While Aza restores GSDME expression, TiO₂ generates reactive oxygen species (ROS) under ultrasound stimulation, activating caspase-3 and inducing pyroptosis via GSDME cleavage. In an orthotopic breast cancer model, HTA enhanced anti-tumor immunity and improved the efficacy of sonodynamic therapy (SDT). This approach presents a novel strategy for augmenting SDT through epigenetically induced pyroptosis.