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

Cancer-associated fibroblasts (CAFs) are heterogeneous and critical drivers of tumor progression, yet engineering tumor-promoting CAF subtypes in situ offers an untapped therapeutic opportunity. Herein, we verify that the FAP+αSMA+ CAFs subtype in the 4T1 murine model effectively recapitulates its counterpart in human triple-negative breast cancer (TNBC), demonstrating strong tumor-promoting activity. We specifically engineer these CAFs in situ to enhance antitumor immunity using an innovative nanodrug, IL-15 plasmid-loaded FAP-sensitive MgCa/z-Gly-Pro-pamidronate acid nanoparticles (PN/MCG NPs). PN/MCG NPs can reverse the tumor-promoting phenotype of FAP + αSMA + CAFs and engineer FAP + αSMA + CAFs to sustain IL-15 expression. These engineered FAP + αSMA + CAFs significantly reduce the tumor immune suppression. Gene set enrichment analysis (GSEA) reveals enhanced immune cell proliferation and activation. Furthermore, we also prove that FAP + αSMA + human mammary fibroblast cells (FAP + αSMA + HMFs) also can be engineered by PN/MCG NPs in vitro . Our findings demonstrate that in situ CAF engineering is a promising strategy to remodel the tumor microenvironment and enhance immunotherapy in TNBC.