Cell Membrane-Camouflaged Cascade Nanozymes Remodel the Hypoxic Tumor Microenvironment for Enhanced Immunotherapy

Abstract

The hypoxic tumor microenvironment (TME) represents a critical barrier to effective immunotherapy in breast cancer. To address this challenge, we design a cell membrane-camouflaged cascade nanozyme (CMAA) that integrates metabolic reprogramming, oxygen regulation, and immunogenic cell death (ICD) induction. CMAA incorporates MnO₂ nanoparticles with catalase-like activity and Au nanoparticles that mimic glucose oxidase (GOx), establishing a sequential catalytic cascade that alleviates hypoxia, depletes glucose, and generates cytotoxic hydroxyl radicals (^•OH). To further optimize oxygen utilization, atovaquone (ATO), a mitochondrial complex III inhibitor, is introduced to suppress cellular oxygen consumption, thereby synergizing with the catalytic process to enhance oxygen availability. Both in vitro and in vivo, CMAA nanozyme effectively reverses hypoxia, induces ICD characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, and promotes CD8⁺ T-cell infiltration. In 4T1 murine breast cancer models, CMAA nanozyme achieves significant tumor growth inhibition, reduces lung metastasis (fewer nodules), and elicits abscopal effects on distant tumors. This work establishes a triple-pathway strategy─simultaneously targeting oxygen supply, oxygen demand, and ^•OH amplification─to reprogram the immunosuppressive hypoxic TME. Through oxygen modulation and immune reprogramming, CMAA nanozyme provides a versatile platform for enhancing breast cancer immunotherapy.