Reversible Metal Coordination Switch Enables Activatable Sonodynamic Therapy via Dual‐Death and Immune Synergy

ABSTRACT Sonodynamic therapy (SDT) holds great potential for disease treatment, yet its efficacy is limited by constitutive reactive oxygen species (ROS) generation and poor selectivity. Herein, we report a generalizable strategy using reversible metal‐ion coordination to regulate the sonodynamic activity of semiconducting polymers (SPs). A diketopyrrolopyrrole (DPP)‐based polymer (SPC) serves as the coordination scaffold, where binding with transition metal ions (Cu 2+ , Co 2+ , Zn 2+ , Fe 3+ ) redistributes electron density and increases the singlet–triplet energy gap (Δ E ST ), thereby effectively suppressing ROS generation. Among them, Cu 2+ is selected as a model ion due to its reductive responsiveness to glutathione (GSH) in the tumor microenvironment (TME). This enables SPCu to remain inactive during systemic circulation and become selectively reactivated within the TME. Released copper further induces mitochondrial dysfunction and cuproptosis, synergizing with ultrasound‐triggered ROS‐driven PANoptosis. Together, this dual‐death mechanism elicits robust tumor ablation, immunogenic cell death, and immune cell activation, leading to systemic antitumor immunity. Collectively, this study presents a reversible, metal coordination–based platform for constructing activatable organic sonosensitizers, offering precise SDT with immuno‐therapeutic synergy.