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Multi\u2010omics sequencings, integrating spatial transcriptomics, metabolomics, single\u2010cell RNA sequencing, bulk proteomics, and metabolomics, are conducted to analyze tumor and blood specimens from 34 patients with NSCLC with or without BMs from the Xiangya Hospital NSCLC (XY\u2010NSCLC) and Queen Mary Hospital NSCLC (QMH\u2010NSCLC) cohorts. This investigation identified\n                    <jats:italic>LOX<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    Malig\u20105 cells as metastasis\u2010initiating cells (MICs) that are significantly associated with poor prognosis. MICs colocalize with specific neutrophil subtypes, which facilitate the formation of neutrophil extracellular traps (NETs) within the metastatic niche. Mechanistically, a NET\u2010KRT10 signaling axis that mediates the interaction between NET\u2010releasing neutrophils and\n                    <jats:italic>LOX<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    Malig\u20105 cells is discovered, thereby promoting epithelial\u2013mesenchymal transition (EMT) and metastasis. Furthermore, metabolic profiling reveals elevated palmitic acid levels in the resulting metastatic niche, which emerges as a crucial metabolic driver in BMs. Using an AI\u2010driven prediction model and in vitro\/in vivo assays, fatty acid synthase inhibitor TVB\u20102640 is identified as a potential therapeutic agent for disrupting metabolic vulnerability and suppressing NSCLC BMs. These findings provide novel insights into NET\u2010dependent cellular interactions that sustain the pro\u2010metastatic microenvironment underlying NSCLC BMs, offering robust development of novel metabolism\u2010based therapeutic strategies to combat this lethal complication.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508478","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:44:16Z","timestamp":1763459056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neutrophil Extracellular Trap Reprograms Cancer Metabolism to Form a Metastatic Niche Promoting Non\u2010Small Cell Lung Cancer Brain Metastasis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0812-5775","authenticated-orcid":false,"given":"Bo","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Xiangya Hospital Central South University  87 Xiangya Road Changsha Hunan 410008 China"},{"name":"Department of Surgery School of Clinical Medicine LKS Faculty of Medicine The University of Hong Kong Queen Mary Hospital  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karrie M.","family":"Kiang","sequence":"additional","affiliation":[{"name":"Department of Surgery School of Clinical Medicine LKS Faculty of Medicine The University of Hong Kong Queen Mary Hospital  Hong Kong SAR 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