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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Bladder cancer presents poor prognosis due to its immunosuppressive microenvironment and resistance to therapies.
• Low response rates to immune checkpoint inhibitors (ICIs) and limited drug delivery strategies hinder effective treatment.
• Developing advanced delivery systems is crucial for overcoming these challenges in bladder cancer therapy.

Purpose of the Study:

• To engineer a mannose-modified, pH/glutathione (GSH) dual-responsive nano-delivery system (MPP@IKE-aPD-1/diABZI).
• To synergistically activate ferroptosis and immune responses for efficient bladder cancer antitumor therapy.
• To enhance the efficacy of immune checkpoint inhibitors (ICIs) and address drug delivery limitations.

Main Methods:

• Co-loading a ferroptosis inducer (IKE), STING agonist (diABZI), and anti-PD-1 antibody (aPD-1) into a Mannose-PEG-s-s-PCL/CDM-PEG-PCL nanocarrier.
• Utilizing a dual-responsive system for tumor microenvironment-specific release and lymph node-targeted delivery.
• Evaluating in vitro drug release, cancer cell ferroptosis induction, and immune cell activation.

Main Results:

• Demonstrated rapid drug release under acidic/high GSH conditions, inducing cancer cell ferroptosis and activating dendritic cells.
• Achieved significant tumor growth inhibition (94.5%) and lung metastasis reduction (92%) in orthotopic mouse models.
• Showcased enhanced CD8+ T cell infiltration, alleviated immunosuppression via PD-1/PD-L1 blockade, and established long-term immune memory.

Conclusions:

• The developed nanosystem offers an innovative multi-mechanism synergistic strategy against bladder cancer immunotherapy resistance.
• This approach demonstrates significant potential for clinical translation in treating bladder cancer.
• The combination of ferroptosis induction and immune response activation presents a promising therapeutic avenue.