PET imaging-guided biomimetic nanoplatform reprograms the tumor immune microenvironment and disrupts stromal barriers to potentiate immunotherapy in malignancy

The fibrotic tumor microenvironment (TME) in triple-negative breast cancer (TNBC) poses a major obstacle to immunotherapy by restricting immune cell infiltration and promoting immune evasion. Here, we develop a biomimetic nanoplatform (CPZT) that combines homologous cancer cell membrane camouflage with pH-responsive drug delivery, enabling tumor-specific and sustained antifibrotic activity within the fibrotic TME. Encapsulation of the antifibrotic agent tranilast within a ZIF-8 core achieves spatiotemporally controlled extracellular matrix remodeling and cancer-associated fibroblast (CAF) suppression. Mechanistically, CPZT disrupts TGF-β/Smad signaling by inhibiting Smad2 phosphorylation and downregulating key CAF markers (α-SMA, FAP, PDGFRα, and LRRC15), thereby reducing the secretion of immunosuppressive cytokines IL-6 and SFRP2, promoting vascular normalization (elevated CD31), decompressing the tumor stroma, and enhancing immune cell infiltration. When combined with PD-1 blockade or γδ T cell therapy, CPZT significantly enhances cytotoxic T cell infiltration and antitumor efficacy accordingly. Furthermore, multimodal PET imaging with tailored tracers ([ 68 Ga]Ga-FAPI-04, [ 68 Ga]Ga-GZP, and [ 68 Ga]Ga-LLP2A) enables noninvasive, dynamic visualization of stromal remodeling and immune activation, with imaging biomarkers correlating strongly with therapeutic responses. This approach addresses fibrosis-driven immunotherapy resistance and provides a precision-guided strategy for stromal–immune modulation in desmoplastic tumors, underscoring the translational potential of integrating biomimetic nanomedicine with functional molecular imaging.