Quantity‐Quality Dual‐Regulation Strategy: Enzyme‐Like Nanoclusters for Improved Cancer Immunotherapy

ABSTRACT Cancer immunotherapy faces significant challenges in breast cancer treatment. Cuproptosis‐triggered immunogenic cell death (ICD) offers a novel strategy for tumor immunotherapy. However, its clinical application encounters two significant challenges. Firstly, the immune activator ATP released during ICD process is converted into immunosuppressive adenosine (ADO) within tumor microenvironment (TME) through the CD39/CD73 exonucleosidase cascade reaction. Secondly, T cells isolated by bone marrow restrict the infiltration of effector T cells into tumors. To address these, we designed enzyme‐like Au‐SS‐Cu@PEG nanoclusters (ACSP NCs) for a “cuproptosis‐ATP/ADO metabolic reprogramming‐T cell chemotaxis” cascade amplification strategy. Upon accumulation within TME, ACSP NCs release Cu 2 + to trigger cuproptosis and ICD, inducing ATP release for dendritic cells (DC) maturation. Furthermore, ACSP NCs exhibit enzyme‐like activity, alleviating tumor hypoxia and downregulating CD39/CD73 expression, reducing ADO levels to 30% of the control group. To achieve systemic immune activation, paroxetine (PX) co‐administration targets the S1P/S1PR1 axis, disrupting the bone marrow retention, thereby increasing T cell populations within the lymphatic circulation, and significantly enhancing tumor infiltration of CD8 + T cells. By combining both “Quantity Regulation” (increased T cell quantity) and “Quality Regulation” (activated T cell function) within the TME, our approach provides a powerful approach for overcoming immune suppression and boosting cancer immunotherapy.