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Immunotherapy for colorectal cancer (CRC) is still clinically limited by the highly immunosuppressive tumor microenvironment. Fusobacterium nucleatum (Fn) selectively colonizes CRC tumors and drives immune suppression by persistently residing in macrophages and promoting their M2 polarization. We designed a self-activating polymeric nanozyme composed of an iron-containing sugar polymer loaded with artesunate (AS) to eliminate intracellular Fn reservoirs in macrophages and reprogram the macrophage immune ecosystem.These nanozymes are specifically phagocytosed by M2-like Fn-infected macrophages through mannose receptor-mediated endocytosis, and are subsequently activated by overexpressed intracellular hydrogen peroxide, releasing ferrous ions and AS, which synergistically amplify the cytotoxic reactive oxygen species (ROS) production through Fenton chemistry. Meanwhile, AS induces macrophage autophagy, promoting the co-localization of nanozymes and bacteria within autophagosomes, thereby enhancing ROS-mediated Fn killing. Notably, the eradication of intracellular Fn not only reverses the immunosuppressive phenotype of infected macrophages but also triggers paracrine signaling that drives M1 repolarization in neighboring uninfected macrophages. In xenograft and orthotopic CRC models containing intracellular Fn, the nanozymes efficiently eliminate intracellular Fn and systematically reshape macrophage immune architecture, significantly enhancing the therapeutic effect of anti-CD47 immunotherapy. This study proposes a strategy to improve CRC immunotherapy by precisely targeting bacteria within tumor-associated macrophages.
