Lighting up Macrophage Reprogramming Assists Immunosuppressive Niche Modulation in Primary Tumors and Tumor‐Draining Lymph Nodes of Breast Cancer

ABSTRACT The recurrence and metastasis of breast cancer are driven by immunosuppressive myeloid cells in tumors and lymph nodes. The inherent heterogeneity of myeloid cells poses a significant challenge for real‐time imaging and precise treatment. In this study, we developed microenvironment‐responsive second near‐infrared (NIR‐II) biomimetic nanoparticles (PA NPs) to spatiotemporally modulate macrophage‐mediated immunotherapies. These NIR‐II activatable “off–on” PA NPs accumulate in tumors and lymph nodes, enabling controlled immune activation. By incorporating colony‐stimulating factor 1 receptor inhibitors, PA NPs repolarized M2‐like macrophages toward the pro‐inflammatory M1‐like phenotype. The subsequent production of nitric oxide (NO) specifically illuminated the NIR‐II fluorescence of PA NPs, thereby providing dynamic visualization of macrophage migration and polarization in vivo. Moreover, PA NPs functionalized with anti‐CD47 antibodies selectively bound to tumor cells, blocked the CD47‐SIRPα “don't eat me” signal, and actively reprogrammed macrophages to enhance phagocytic clearance of tumor cells. In multiple breast cancer models, these nanoparticles effectively remodeled immunosuppressive niches and induced durable anti‐tumor immunity, which was further validated using patient‐derived tumor and lymph node fragments. Collectively, this strategy integrates NIR‑II–guided diagnosis and macrophage reprogramming therapy to remodel the immunosuppressive microenvironment across primary and metastatic niches, offering a potent immunotherapeutic approach against breast cancer.