Switchable Enzyme‐Regulated ECM‐Integrin‐Cholesterol Signaling Orchestrate PD‐L1 Dual Destabilization for Boosting Photo‐Immunotherapy

ABSTRACT Although PD‐1/PD‐L1 blockade therapy has shown clinical success, its efficacy in solid tumors remains limited by the immunosuppressive tumor microenvironment. The tumor extracellular matrix (ECM), which forms a dense physical barrier and activates integrin‐mediated mechanotransduction to upregulate PD‐L1, while cholesterol‐enriched membrane domains stabilize integrin clustering and PD‐L1 localization, forming a self‐reinforcing ECM‐integrin‐cholesterol signaling network that drives immune evasion. Here, we designed a switchable natural enzyme nanoplatform with dual safety locks, co‐delivering papain and cholesterol synthesis inhibitor simvastatin to disrupt this network at multiple levels. Papain remains inactive during systemic circulation and intracellular trafficking, ensuring biosafety, but is selectively activated by tumor‐released glutathione and boosted by localized photothermal heating to precisely degrade ECM, suppressing integrin signaling and PD‐L1 transcription, while simvastatin‐driven cholesterol depletion amplifies this effect by destabilizing integrin clusters and promoting PD‐L1 degradation. Combined with phototherapy‐induced immunogenic cell death, this strategy remodels ECM, enhances T cell infiltration, overcomes checkpoint blockade resistance, and eradicates advanced tumors (∼500 mm 3 ).