Engineering NK cell membrane-camouflaged copper-BODIPY nanoassembly to synergize dual-phototherapy and cuproptosis for enhanced antitumor immunity

Cuproptosis, a copper-dependent form of programmed cell death, has emerged as a promising strategy to activate anti-tumor immunity through immunogenic cell death (ICD). However, its efficacy is often hindered by insufficient copper accumulation and glutathione-mediated copper chelation in tumor cells. Herein, we present an NK cell membrane-camouflaged copper‑boron dipyrrolylmethyl (BODIPY) coordinated nanoassembly to facilitate the tumor-targeted delivery of copper and integrate dual-wavelength phototherapy to potentiate cuproptosis and enhance antitumor immunity for synergistic cancer therapy. The nanoplatform enables 658 nm laser-triggered photodynamic therapy (PDT) to generate reactive oxygen species and 1064 nm laser-induced mild photothermal therapy (PTT) to produce localized hyperthermia. The combined PDT/PTT treatment not only produces direct cytotoxicity against tumor cells, but also depletes intracellular glutathione through oxidative stress, preventing copper chelation to amplify cuproptosis. This multimodal approach triggers robust ICD, driving dendritic cell maturation, macrophage polarization, tumor-infiltrating lymphocyte activation and pro-inflammatory cytokines secretion. Consequently, the immunosuppressive tumor microenvironment is remodeled, eliciting a strong and durable anti-tumor immune response that effectively inhibits tumor growth and prevents tumor recurrence and metastasis. Overall, this study proposes a novel strategy to potentiate cuproptosis-mediated ICD for synergistic cancer therapy.