Cascade-Responsive Nanoprodrug Disrupts Immune-Fibroblast Communications for Potentiated Cancer Mechanoimmunotherapy

Area of Science:

• Oncology
• Immunology
• Materials Science

Background:

• Desmoplastic tumors present significant challenges due to their abnormal mechanical microenvironment and low immunogenicity, hindering effective immune responses.
• Cancer-associated fibroblasts (CAFs), particularly the FAP-α+ subset, contribute to stromal stiffness, which impedes cytotoxic T lymphocyte infiltration and promotes tumor progression.
• Inefficient conversion of chemotherapeutic agents within tumors also limits their efficacy and contributes to poor immunogenicity.

Purpose of the Study:

• To design and evaluate a cascade-responsive nanoprodrug for potentiating cancer mechanoimmunotherapy in desmoplastic tumors.
• To investigate the dual action of the nanoprodrug in re-educating FAP-α+ CAFs and amplifying tumor immunogenicity.
• To overcome resistance to immune checkpoint inhibitors in preclinical models of triple-negative breast cancer.

Main Methods:

• Development of a novel nanoprodrug incorporating an angiotensin II receptor antagonist (losartan) and a topoisomerase I inhibitor (7-Ethyl-10-hydroxycamptothecin).
• Utilized FAP-α cleavable peptide for targeted release of losartan and leveraged high intracellular glutathione/esterase for prodrug activation.
• Assessed the therapeutic efficacy in mice with triple-negative breast cancer, evaluating primary tumor growth and response to immune checkpoint inhibitors.

Main Results:

• The nanoprodrug successfully re-educated FAP-α+ CAFs, reducing stromal stiffness and facilitating cytotoxic T lymphocyte infiltration.
• Efficient conversion of the chemotherapeutic prodrug within tumor cells amplified tumor immunogenicity.
• The treatment retarded primary tumor growth and significantly counteracted resistance to immune checkpoint inhibitors in preclinical models.
• The developed regimen created an immune-activated landscape conducive to tumoricidal immunity.

Conclusions:

• Nanoprodrug-assisted mechanoimmunotherapy is a promising strategy for treating desmoplastic tumors by modulating the tumor microenvironment and enhancing anti-tumor immunity.
• This approach offers a universal strategy for overcoming immune exclusion in desmoplastic tumors.
• The findings suggest a potential new avenue for improving the efficacy of cancer immunotherapy, particularly in challenging tumor types.