Reactive oxygen species-responsive dual-targeted nanosystem promoted immunogenic cell death against breast cancer

Area of Science:

• Oncology
• Immunology
• Nanotechnology
• Materials Science

Background:

• Optimizing breast cancer treatment remains challenging, with poor antigen presentation hindering effective cancer immunotherapy.
• Developing strategies to enhance immune cell infiltration and activation is crucial for improving therapeutic outcomes.

Purpose of the Study:

• To develop a synergistic immunotherapy for breast cancer using a reactive oxygen species (ROS)-responsive dual-targeted nanosystem.
• To simultaneously release doxorubicin (DOX), R848, and MIP-3α, promoting immune cell infiltration, immunogenic cell death (ICD), and dendritic cell (DC) maturation.

Main Methods:

• A dual-targeted, ROS-responsive thioketal nanoparticle (TKNP) system was engineered, loaded with DOX, R848, and MIP-3α, and conjugated with anti-PD-L1.
• The nanosystem was evaluated for its ability to induce ICD, promote DC maturation, and enhance immune cell infiltration in a breast cancer model.
• Mechanistic studies investigated tumor targeting, calreticulin (CRT) and HMGB1 exposure, and the infiltration of CD4+ and CD8+ T cells.

Main Results:

• Intratumoral injection of the anti-PD-L1-DOX-R848-MIP-3α/TKNP system led to significant breast cancer regression.
• The nanosystem effectively targeted tumor tissues, maximizing CRT and HMGB1 exposure.
• Significant enhancement of intratumoral CD4+ and CD8+ T cell infiltration was observed.

Conclusions:

• The developed ROS-responsive TKNP system offers a promising synergistic immunotherapy strategy for breast cancer.
• This approach effectively modulates the tumor microenvironment by combining ICD, immune cell recruitment, and DC maturation.
• The dual-targeted nanosystem represents a potential clinical treatment strategy for effective breast cancer management.