A nuclei bombing nano-system improves STING-activated cancer immunotherapy

Abstract

The activation of the stimulator of interferon genes (STING) pathway presents a promising therapeutic strategy for pancreatic cancer by enhancing immune responses and reprogramming the immunosuppressive tumor microenvironment (TME). Ferroptosis, an iron-dependent form of cell death, can synergize with STING activation through reactive oxygen species (ROS)-induced DNA damage. However, its efficacy is hindered by poor vascularization, inefficient delivery of STING agonists, and tumor resistance mechanisms that suppress ROS levels. To overcome these limitations, we developed a "nuclei bombing" nano-system using extremely small cuprous oxide modified magneto-human heavy chain ferritin (ES-CO@M-HFn). This system targets pancreatic cancer cells overexpressing transferrin receptor 1 (TfR1) and releases Cu⁺ and Fe³⁺ ions in response to the acidic (pH 6.8) and glutathione (GSH)-rich TME. These ions form a Cu-Fe catalytic cycle under high H₂O₂ levels, continuously generating Fe²⁺, Cu⁺, and robust ROS, thereby inducing ferroptosis and cuproptosis. This creates a synergistic feedback loop that amplifies oxidative damage, leading to extensive DNA damage and tumor cell destruction—termed the "nuclei bombing" effect. The resulting DNA fragments activate the STING pathway, reprogramming the TME by maturing dendritic cells, repolarizing macrophages, and activating CD8⁺ T cells. This comprehensive approach generates a potent immune response, significantly suppressing tumor growth and metastasis, and offers a transformative strategy for pancreatic cancer treatment.