Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunology

Background:

• Immunotherapy is a key cancer treatment, but tumor microenvironment (TME) heterogeneity limits its effectiveness.
• Developing strategies to overcome immune escape and enhance immunotherapy is crucial for broader clinical success.

Purpose of the Study:

• To develop a TME-responsive nanoparticle for codelivering interleukin-12 (IL-12) gene and CSF-1R inhibitor PLX3397 (PLX).
• To enhance anti-tumor immunity and reverse immune escape by modulating the TME.

Main Methods:

• Fabrication of nanoparticles with disulfide bonds for reactivity and cRGD peptides for tumor targeting.
• Codelivering IL-12 expressing gene and PLX3397 to activate host immunity and inhibit CSF-1R signaling.
• Utilizing single-cell analysis to decipher TME changes, including cell infiltration, transcriptional states, and signaling.

Main Results:

• The functional nanoparticle ameliorated the TME by stimulating T lymphocytes and dendritic cells (DCs).
• It promoted TAM repolarization, reduced myeloid-derived suppressor cells (MDSCs), and enhanced anti-tumor cytokine secretion.
• Efficient suppression of tumor growth and metastasis was observed, with significant TME modulation confirmed by single-cell analysis.

Conclusions:

• The developed nanoparticle represents a promising combinatorial immunotherapy strategy for cancer treatment.
• Modulating the TME through targeted delivery of IL-12 and CSF-1R inhibitors offers a feasible approach to enhance anti-tumor immunity.
• Single-cell analysis provides deep insights into nanoparticle-mediated TME reprogramming and therapeutic effects.