Review of Copper-Based Nanozymes for Remodeling the Tumor Immune Microenvironment

Cuproptosis is a regulated cell death process triggered by intracellular copper overload and contingent upon mitochondrial respiration, in which copper binding to lipoylated TCA cycle proteins causes proteotoxic stress. Copper-based nanozymes provide a strategy to couple copper delivery with tumor microenvironment-responsive catalysis. Peroxidase- and oxidase-like activities can promote hydroxyl radicals or other reactive oxygen species generation for chemodynamic therapy, whereas catalase- or superoxide dismutase-like activities mainly regulate redox balance, supply oxygen, and relieve hypoxia to support photodynamic therapy, radiotherapy, or starvation therapy combinations. In responsive nanoplatforms, catalytic activity, glutathione depletion, and controlled copper-ion release can be integrated to amplify oxidative stress, perturb copper homeostasis, and induce cuproptosis. These events may promote immunogenic cell death, dendritic cell maturation, CD8+ T-cell infiltration, macrophage repolarization, and attenuation of immunosuppressive cell populations, thereby remodeling the tumor immune microenvironment. This Review systematically examines design strategies for copper-based nanozymes, elucidates the molecular mechanisms underlying multimodal synergistic therapy, and provides a critical perspective on overcoming current bottlenecks to accelerate clinical implementation.