Highly Active Cu ₁₄ Cluster Precisely Activates Autophagy Inhibitor to Amplify Cuproptosis Immunotherapy

ABSTRACT Transition metal‐mediated cleavage mechanisms have emerged as an effective means to mitigate the off‐target toxicity of conventional therapeutic agents. However, the utilization of non‐essential metal catalysts and suboptimal catalytic efficiency often compromises their therapeutic efficacy. Given the critical role of copper in biological processes and the high catalytic activities of atomically precise copper clusters rich in Cu ⁺ , herein, a Cu ₁₄ cluster‐mediated cleavage reaction is first employed for synergistic cuproptosis‐associated immunogenic cell death (ICD) induction with localized autophagy suppression to intensify immunotherapy effects. To endow homologous targeting capability, the Cu ₁₄ cluster is camouflaged with cancer cell membrane, obtaining Cu ₁₄ @CM. Upon tumor accumulation, the pH‐sensitive Cu ₁₄ @CM releases copper ions to trigger cuproptosis through lipoylated protein oligomerization and iron‐sulfur cluster protein disruption, further releasing damage‐associated molecular patterns (DAMPs) and generating robust ICD. Simultaneously, the cluster catalyzes bond cleavage reactions to produce autophagy inhibitors, blocking cytoprotective autophagy to amplify DAMPs exposure. This dual‐action strategy increases dendritic cell maturation, and elevates tumor‐infiltrating cytotoxic T lymphocytes, thereby reinforcing the antitumor immune response.