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The unique microenvironment of the brain plays a critical role in the initiation and progression of brain metastases (BM), yet the molecular mechanisms underlying tumor-microenvironment interactions remain poorly understood. Here, we demonstrate that upregulation of lipocalin-2 (LCN2) in tumor cells promotes brain metastatic progression by orchestrating crosstalk among metastatic tumor cells, astrocytes, and macrophages. Brain metastatic tumor cells secrete LCN2, which binds to SLC22A17 on astrocytes, activating JAK2\/STAT3 signaling and inducing astrocyte activation and chemokine secretion, thereby facilitating macrophage recruitment. In turn, macrophages secrete IL-1\u03b2, which further upregulates LCN2 expression in tumor cells. Prophylactic administration of the IL-1 receptor antagonist anakinra inhibits BM formation, whereas therapeutic administration alone is ineffective. However, treatment with the STAT3 inhibitor SH4-54, either alone or in combination with anakinra, significantly suppressed tumor growth in the BM. Furthermore, tumor-secreted LCN2 can bind to SLC22A17 on tumor cells, activating JAK2\/STAT3 signaling and promoting VEGF-A expression and release, which enhances tumor neovascularization. Inhibition of this axis with SH4-54, bevacizumab, or their combination effectively reduces the tumor burden in BM-bearing mice. These findings underscore the central role of LCN2 in driving brain metastasis and highlight a potential therapeutic strategy for targeting brain metastatic lung cancer.<\/jats:p>","DOI":"10.1038\/s41392-025-02514-2","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:01:59Z","timestamp":1766534519000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Yixiang","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danming","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqing","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sini","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianchun","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixiao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,24]]},"reference":[{"key":"2514_CR1","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1200\/JCO.1988.6.9.1474","volume":"6","author":"JB Sorensen","year":"1988","unstructured":"Sorensen, J. 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