In Situ Remodeling of Tumor Microenvironment via Specific Cancer-Associated Fibroblasts Subtype Engineering to Boost...

Area of Science:

• Oncology
• Immunology
• Nanotechnology

Background:

• Cancer-associated fibroblasts (CAFs) are key drivers of tumor progression.
• Heterogeneity in CAFs presents challenges for cancer therapy.
• Targeting specific CAF subtypes offers a therapeutic opportunity.

Purpose of the Study:

• To engineer tumor-promoting FAP+αSMA+ CAFs in situ to enhance antitumor immunity.
• To investigate the potential of nanodrugs for in situ CAF modulation.
• To assess the efficacy of engineered CAFs in triple-negative breast cancer (TNBC).

Main Methods:

• Utilized FAP-sensitive MgCa/z-Gly-Pro-pamidronate acid nanoparticles (PN/MCG NPs) loaded with IL-15 plasmid.
• Engineered FAP+αSMA+ CAFs in situ in the 4T1 murine model.
• Validated CAF engineering in vitro using human mammary fibroblast cells (HMFs).
• Analyzed immune cell activity using Gene Set Enrichment Analysis (GSEA).

Main Results:

• PN/MCG NPs successfully reversed the tumor-promoting phenotype of FAP+αSMA+ CAFs.
• Engineered CAFs sustained IL-15 expression, reducing tumor immune suppression.
• Demonstrated enhanced immune cell proliferation and activation.
• Confirmed successful in situ and in vitro CAF engineering.

Conclusions:

• In situ CAF engineering is a viable strategy to remodel the tumor microenvironment.
• This approach holds promise for enhancing immunotherapy in TNBC.
• Targeted modulation of CAFs can overcome tumor-induced immunosuppression.