{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:45:08Z","timestamp":1792136708935,"version":"4.4.0"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"abstract":"Abstract<\/jats:title>\n \n Forkhead box protein C2 (FOXC2) is frequently overexpressed in osteosarcoma (OS) and has been implicated in tumor proliferation and metastasis; however, its role in regulating the tumor immune microenvironment remains poorly understood. In this study, integrative bioinformatics analyses of the TCGA\u2010SARC (The Cancer Genome Atlas sarcoma cohort) dataset were performed to evaluate the clinical significance of\n FOXC2<\/jats:italic>\n in OS. High\n FOXC2<\/jats:italic>\n expression was significantly associated with poorer overall survival in patients with OS (\n p<\/jats:italic>\n \u2009<\u20090.001). Functional experiments demonstrated that\n FOXC2<\/jats:italic>\n knockdown significantly reduced the overall viable cell\/metabolic signal, migration, and invasion in U\u20102 OS and SaOS\u20102 cells (\n p<\/jats:italic>\n \u2009<\u20090.05). Mechanistically,\n FOXC2<\/jats:italic>\n was found to regulate the CXCL12\/CXCR4 signaling axis. ELISA, RT\u2010qPCR, and western blotting analyses showed that\n FOXC2<\/jats:italic>\n knockdown decreased CXCL12 expression, whereas\n FOXC2<\/jats:italic>\n overexpression significantly increased CXCL12 levels. ChIP\u2010qPCR analysis demonstrated significant enrichment of\n FOXC2<\/jats:italic>\n at the\n CXCL12<\/jats:italic>\n promoter and detectable enrichment at the\n CXCR4<\/jats:italic>\n promoter in SaOS\u20102 cells, and dual\u2010luciferase reporter assays further showed that\n FOXC2<\/jats:italic>\n overexpression significantly increased\n CXCL12<\/jats:italic>\n promoter activity whereas\n FOXC2<\/jats:italic>\n knockdown reduced it, supporting direct transcriptional regulation of the CXCL12\/CXCR4 axis by FOXC2. In macrophage co\u2010culture experiments,\n FOXC2<\/jats:italic>\n knockdown promoted M1\u2010like macrophage polarization and reduced M2\u2010like macrophage markers, whereas activation of CXCR4 partially reversed these effects. Flow cytometric analysis further confirmed that\n FOXC2<\/jats:italic>\n knockdown significantly increased the M1\/M2 macrophage ratio.\n In vivo<\/jats:italic>\n ,\n FOXC2<\/jats:italic>\n knockdown markedly reduced tumor growth and lung metastases in a xenograft mouse model, with tumor volume and lung metastatic burden reduced by approximately 50% and 43%, respectively. Tumor tissues from\n FOXC2<\/jats:italic>\n \u2010knockdown mice exhibited increased M1\u2010like macrophage infiltration and reduced M2\u2010like macrophage markers. Together, these findings demonstrate that FOXC2 regulates macrophage polarization and OS progression through transcriptional modulation of the\n CXCL12\/CXCR4<\/jats:italic>\n signaling axis, highlighting FOXC2 as a potential regulator of the tumor immune microenvironment in OS. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n <\/jats:p>","DOI":"10.1002\/path.70137","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:50:48Z","timestamp":1792133448000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXC2<\/scp>\n regulates macrophage polarization and osteosarcoma progression via the\n CXCL12<\/scp>\n \/\n CXCR4<\/scp>\n signaling axis"],"prefix":"10.1002","author":[{"given":"Wei","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahui","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokun","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4473-8923","authenticated-orcid":false,"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine The First Affiliated Hospital of Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2020.12.024","article-title":"Immunotherapy for osteosarcoma: fundamental mechanism, rationale, and recent breakthroughs","volume":"500","author":"Chen C","year":"2021","journal-title":"Cancer Lett"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.biomaterials.2024.122675","article-title":"In situ hydrogel based on Cu\u2010Fe3O4 nanoclusters exploits oxidative stress and the ferroptosis\/cuproptosis pathway for chemodynamic 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