Reprogramming the Immunosuppressive Microenvironment in Triple-Negative Breast Cancer via FAP-Targeted Nanoprobes for Multimodal Imaging and Photothermal Therapy.

Abstract

Triple-negative breast cancer (TNBC) poses a major clinical challenge because of its aggressive behavior, high likelihood of metastasis, and absence of specific therapeutic targets. The immunosuppressive tumor microenvironment, largely influenced by cancer-associated fibroblasts (CAFs) through fibroblast activation protein (FAP)-mediated extracellular matrix (ECM) remodeling and cytokine secretion, contributes to TNBC's resistance to immunotherapy. In response to this challenge, we have developed FAP-targeted nanoprobes (FAP-IR1061) that incorporate second near-infrared (NIR-II) fluorescence/magnetic resonance (MR)/photoacoustic (PA) imaging capabilities alongside highly efficient NIR-II photothermal conversion for precision theranostics. This platform facilitates a tripartite therapeutic approach: (1) selective ablation of CAFs and dismantling of the ECM to overcome physical barriers; (2) spatiotemporal induction of immunogenic cell death through the release of damage-associated molecular patterns; (3) functional repolarization of tumor-associated neutrophils toward antitumor N1 phenotypes. When used in conjunction with anti-programmed cell death protein 1 (αPD-1) therapy, this strategy achieves over 80% suppression of both primary and distant tumors by enhancing the infiltration of cytotoxic T lymphocytes. Collectively, these effects promote the establishment of long-term antitumor immune memory, which facilitates tumor eradication and prevents tumor recurrence.