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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,9]]},"abstract":"<jats:p>\n                    Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet their molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial\u2013mesenchymal transition (EMT) and cancer stemness. Recent single-cell RNA sequencing (scRNA-seq) identified GPNMB as a marker of immunosuppressive TAMs associated with poor prognosis, but its mechanistic role in TNBC has remained unclear. Coculturing monocytic cells with three-dimensional TNBC spheres induced GPNMB\n                    <jats:sup>+<\/jats:sup>\n                    TAMs expressing sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9). Tumor-expressed GPNMB promotes monocyte-to-TAM polarization by inducing secondary GPNMB expression in monocytes, establishing a feed-forward amplification loop. GPNMB knockdown in TNBC cells inhibited immunosuppressive TAM subsets, including Siglec-9\n                    <jats:sup>+<\/jats:sup>\n                    and EMT-associated populations, as determined by deconvolution of bulk RNA-seq data using a custom TAM signature matrix derived from publicly available TNBC scRNA-seq datasets. TNBC-derived GPNMB carried \u03b12,3-sialylation, whereas macrophage-derived GPNMB carried \u03b12,6-sialylation, enabling differential Siglec-9 recognition. Elevated GPNMB and Siglec-9 correlated with poor prognosis in TNBCcohorts. Importantly, dual inhibition of Siglec-E (murine Siglec-9 ortholog) and PD-1 reduced tumor stemness, suppressed IL-6-dependent EMT, and limited lung metastasis in vivo. The GPNMB\u2013Siglec-9 axis thus represents a critical glyco-immunological checkpoint driving TAM-mediated metastasis, providing a promising therapeutic target in TNBC.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2503081122","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T18:00:10Z","timestamp":1756836010000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Tumor-expressed GPNMB orchestrates Siglec-9\n                    <sup>+<\/sup>\n                    TAM polarization and EMT to promote metastasis in triple-negative breast cancer"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0218-6440","authenticated-orcid":false,"given":"Thuy Linh","family":"Dang Cao","sequence":"first","affiliation":[{"name":"Department of Experimental Pathology, Institute of Medicine, University of Tsukuba","place":["Tsukuba, Ibaraki, 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