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The inherent heterogeneity of myeloid cells poses a significant challenge for real\u2010time imaging and precise treatment. In this study, we developed microenvironment\u2010responsive second near\u2010infrared (NIR\u2010II) biomimetic nanoparticles (PA NPs) to spatiotemporally modulate macrophage\u2010mediated immunotherapies. These NIR\u2010II activatable \u201coff\u2013on\u201d PA NPs accumulate in tumors and lymph nodes, enabling controlled immune activation. By incorporating colony\u2010stimulating factor 1 receptor inhibitors, PA NPs repolarized M2\u2010like macrophages toward the pro\u2010inflammatory M1\u2010like phenotype. The subsequent production of nitric oxide (NO) specifically illuminated the NIR\u2010II fluorescence of PA NPs, thereby providing dynamic visualization of macrophage migration and polarization in vivo. Moreover, PA NPs functionalized with anti\u2010CD47 antibodies selectively bound to tumor cells, blocked the CD47\u2010SIRP\u03b1 \u201cdon't eat me\u201d 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\u2010tumor immunity, which was further validated using patient\u2010derived tumor and lymph node fragments. Collectively, this strategy integrates NIR\u2011II\u2013guided diagnosis and macrophage reprogramming therapy to remodel the immunosuppressive microenvironment across primary and metastatic niches, offering a potent immunotherapeutic approach against breast cancer.<\/jats:p>","DOI":"10.1002\/advs.75593","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T10:55:01Z","timestamp":1778064901000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lighting up Macrophage Reprogramming Assists Immunosuppressive Niche Modulation in Primary Tumors and Tumor\u2010Draining Lymph Nodes of Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4865-4137","authenticated-orcid":false,"given":"Yingbo","family":"Li","sequence":"first","affiliation":[{"name":"Department of Radiology Zhongda Hospital Medical School of Southeast University Nurturing Center of 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