Sonosensitizer‐Functionalized Polymetallic Nanoenzymes for Photoacoustic Imaging‐Guided Cancer Sonodynamic Immunotherapy

ABSTRACT Low tumor immunogenicity and limited immune‐cell infiltration remain major barriers to effective breast cancer immunotherapy. Although sonodynamic therapy (SDT) offers a noninvasive strategy for deep‐tissue tumor treatment, its efficacy is often restricted by insufficient reactive oxygen species (ROS) generation and the immunosuppressive tumor microenvironment. Here, we report a sonosensitizer‐functionalized polymetallic nanozyme, Pd@PtBi 2 ‐Ce6@HA (PPBCH), as a multifunctional theranostic platform for photoacoustic imaging‐guided sonodynamic cancer immunotherapy. Upon ultrasound (US) activation, PPBCH exhibits catalase‐, peroxidase‐, and glutathione oxidase‐like activities, thereby enabling O 2 generation, ROS amplification, and intracellular glutathione depletion. This coordinated redox disruption induces mitochondrial dysfunction, lipid peroxidation, and GPX4 downregulation, leading to severe oxidative damage, ferroptotic stress, and subsequent immunogenic cell death. PPBCH also elicits canonical hallmarks of immunogenic cell death, including calreticulin exposure, HMGB1 release, and extracellular ATP secretion, thereby promoting dendritic cell maturation and antitumor immune activation. In parallel, the polymetallic framework enables photoacoustic imaging for monitoring tumor accumulation and guiding treatment timing in vivo. More importantly, PPBCH‐mediated SDT remodels the immunosuppressive tumor microenvironment, enhances CD8 + T‐cell infiltration, promotes M1‐like macrophage polarization, and markedly improves the therapeutic efficacy of anti‐PD‐L1 immunotherapy. This work establishes a polymetallic nanozyme strategy that integrates catalytic sonodynamic amplification, imaging‐guided intervention, and immunomodulation for precise cancer immunotherapy.