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

Abstract

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.