Co-delivery nanoparticle targeting CAF for simultaneous activating T cell plus NKT cell attack in solid tumor

Area of Science:

• Biomedical Engineering
• Cancer Research
• Nanotechnology

Background:

• Tumor fibrosis creates a physical barrier, hindering immunotherapy by limiting immune cell infiltration.
• Overcoming this immunosuppressive barrier is crucial for effective cancer treatment.

Purpose of the Study:

• To develop a fibroblast-activated protein-α (FAP-α) responsive nanoparticle delivery system, (α-GC/NAV)-CPC.
• To encapsulate navitoclax (NAV) and alpha-galactosylceramide (α-GC) for targeted drug release within the tumor microenvironment.

Main Methods:

• Designed amphiphilic block polymers with FAP-α degradable linkers for nanoparticle self-assembly.
• Co-encapsulated NAV and α-GC into FAP-α responsive nanoparticles.
• Validated nanoparticle efficacy in triple-negative breast cancer models.

Main Results:

• The (α-GC/NAV)-CPC system effectively dismantled the FAP-α-positive fibroblast barrier, reducing tumor interstitial fluid pressure by 4.9-fold.
• Achieved significant increases in tumor-infiltrating NKT cells (over 5-fold) and T cells (over 4-fold).
• Demonstrated potent anti-tumor activity, with 66.7% tumor eradication in vivo and reduced pulmonary metastasis.

Conclusions:

• The FAP-α responsive nanoparticle system successfully overcomes tumor fibrosis and enhances anti-tumor immunity.
• This strategy offers a promising approach for improving cancer immunotherapy by targeting the tumor microenvironment.