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Current therapeutic options for brain metastasis remain limited, resulting in poor clinical outcomes. Previous studies have demonstrated that tumor cell invasion into the brain involves localized activation of astrocytes, with these tumor-associated astrocytes (TAAs) exhibiting either pro-tumor or anti-tumor effects. However, the role of astrocytes during postcolonization stages remains unclear. In this study, employing both a murine model of lung cancer brain metastasis and an in vitro coculture system, we identified the presence of astrocytes within the tumor microenvironment of both clinical specimens and experimental models. Our in vitro experiments revealed that astrocytes significantly enhanced tumor cell survival without affecting proliferation, primarily through inhibition of apoptosis. Mechanistic investigations demonstrated that astrocyte-derived TNF-\u03b1 mediates this anti-apoptotic effect via activation of the NF-\u03baB signaling pathway in tumor cells. Genetic knockdown of TNF receptor 2 (TNFR2) in tumor cells or pharmacological inhibition of the NF-\u03baB pathway effectively abolished this protective effect. Importantly, TNFR2 knockdown increased intracranial tumor cell apoptosis and prolonged survival in the brain metastasis mouse model. These findings collectively demonstrate that TAAs in lung cancer brain metastasis promote tumor cell survival through a TNFR2\u2013NF-\u03baB-dependent mechanism mediated by TNF-\u03b1 secretion.<\/jats:p>","DOI":"10.1093\/carcin\/bgaf090","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:10:44Z","timestamp":1765545044000},"source":"Crossref","is-referenced-by-count":2,"title":["Tumor-associated astrocytes inhibit tumor cell apoptosis through TNF-\u03b1\u2013TNF receptor 2\u2013NF-\u03baB pathway in lung cancer brain metastasis"],"prefix":"10.1093","volume":"47","author":[{"given":"Shuo","family":"Zhang","sequence":"first","affiliation":[{"name":"Pediatric Cancer Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123 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Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaonan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Pediatric Cancer Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5084-0804","authenticated-orcid":false,"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Pediatric Cancer Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123 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