Nano-Immunotherapy Synergizing Ferroptosis and STING Activation in Metastatic Bladder Cancer

<b>Background:</b> Bladder cancer is associated with poor clinical prognosis due to their immunosuppressive microenvironment and therapeutic resistance. <b>Methods:</b> To address the low response rate of immune checkpoint inhibitors (ICIs) and the lack of effective drug delivery strategies, this study developed a mannose-modified pH/glutathione (GSH) dual-responsive nano-delivery system (MPP@IKE-aPD-1/diABZI) that synergistically activates ferroptosis and immune responses to achieve efficient antitumor therapy. This nanosystem uses Mannose-PEG-s-s-PCL/CDM-PEG-PCL as carriers to co-load the ferroptosis inducer IKE, STING agonist diABZI, and anti-PD-1 antibody (aPD-1), enabling tumor microenvironment-specific drug release and lymph node-targeted delivery. <b>Results:</b> In vitro experiments demonstrated rapid drug release under acidic/high GSH conditions, inducing ferroptosis in bladder cancer cells and activating dendritic cells through the release of danger signals such as HMGB1. It showed marked enrichment of the nanosystem in tumors and draining lymph nodes, suppressing orthotopic bladder tumor growth (94.5% inhibition rate) and lung metastasis (92% reduction in metastatic foci) while extending median survival in mice to 35 d. Mechanistic studies revealed that ferroptosis-induced immunogenic cell death synergized with STING pathway activation to enhance CD8⁺ T cell infiltration and granzyme B expression, while blocking the PD-1/PD-L1 axis alleviated immunosuppression. Furthermore, the treatment group exhibited long-term immune memory, effectively preventing tumor recurrence. <b>Conclusion:</b> This study provides an innovative multi-mechanism synergistic strategy to overcome immunotherapy resistance in bladder cancer, demonstrating significant clinical translation potential.