Ultrasound Responsive Mn/Se-Nanozyme as PANoptosis Initiators for Bladder Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Bladder cancer presents significant recurrence and mortality challenges.
• Current treatments like surgery and chemotherapy have limitations.
• Immune checkpoint inhibitors (ICIs) show limited efficacy due to poor tumor immune infiltration.

Purpose of the Study:

• To develop an ultrasound-responsive nanozyme for bladder cancer treatment.
• To activate STING signaling and PANoptosis for enhanced anti-tumor immunity.
• To investigate the nanozyme's potential in combination with PD-1 blockade.

Main Methods:

• Development of an ultrasound-responsive Mn/Se-NE@FCS nanozyme.
• In vitro and in vivo studies in murine bladder cancer models.
• Assessment of STING and PANoptosis activation, ROS production, mitochondrial dysfunction, and immunogenic cell death (ICD).
• Evaluation of immune cell infiltration (dendritic cells, CD8+ T-cells) and memory T-cell expansion.
• Histological and flow cytometry analyses of tumor microenvironment modulation.

Main Results:

• The nanozyme effectively activated STING signaling and PANoptosis, inducing multi-pathway cell death.
• Treatment enhanced ROS production, mitochondrial dysfunction, and ICD.
• Nanozyme therapy promoted dendritic cell maturation and increased CD8+ T-cell infiltration.
• Superior tumor control was observed, with significant synergy when combined with PD-1 blockade.
• The treatment successfully remodeled the tumor microenvironment, driving immune activation and T-cell priming.

Conclusions:

• The developed ultrasound-responsive nanozyme is a promising strategy for bladder cancer nanoimmunotherapy.
• Dual activation of STING and PANoptosis effectively induces tumor cell death and systemic immunity.
• This approach offers a novel method to overcome limitations of current bladder cancer treatments and enhance anti-tumor responses.