Utilizing “Delocalized Electron Sailing” Strategy to Modulate Eg Orbital Occupancy of Dual‐Atom Piezo‐Catalyst for Ultrasound‐Enhanced Immunotherapy

ABSTRACT The combination of immunogenic cell death (ICD) and immune checkpoint blockade (ICB) represents a promising strategy for inhibiting tumor growth and metastasis. Herein, we developed a dual‐atom piezo‐catalyst platform (denoted as FeCu–DSPCs) combined with α–PD–1/CTLA–4 to achieve effective immunotherapy against triple‐negative breast cancer. Mechanistically, unlike traditional sonodynamic therapy, FeCu–DSPCs exhibited a robust piezoelectric response through a built‐in polarized electric field without relying on the piezoelectricity of the substrate material, which promoted the valence electron transfer and captured delocalized electrons. This “Delocalized Electron Sailing” (DES) strategy accelerated the rate‐determining step of cascade reactions through the increased, e g, orbital occupancy, resulting in explosive generation of reactive oxygen species (ROS). Therapeutically, FeCu–DSPCs disrupted both the energy metabolism cycle and redox balance, triggering endoplasmic reticulum (ER) stress and the release of damage‐associated molecular patterns (DAMPs). Consequently, potent antitumor immune responses are elicited, including M1 macrophage polarization, dendritic cell (DC) maturation, and enhanced T cell infiltration. The combination of FeCu–DSPCs with α–PD–1/CTLA–4 effectively overcame the immunosuppressive tumor microenvironment and inhibited lung metastasis in mouse models. This work establishes a visionary bridge between dual‐atom catalysts (DACs) and nanomedicine, paving the way for further exploration of carbon‐based piezoelectric phenomena in cancer immunotherapy.