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journal article·2026-01Open access

Neutrophil Extracellular Trap Reprograms Cancer Metabolism to Form a Metastatic Niche Promoting Non‐Small Cell Lung Cancer Brain Metastasis

Bo Chen, Karrie M. Kiang, Fangkun Liu, Chuntao Li, Xizhe Li, Chen Weiwei, Xin Fu, Gelei Xiao, Jingyi Sun, Erhan Da, Junbo Liao, Hongshu Zhou, Li Meng, Li Zhou, Tao Song, Longbo Zhang, Gilberto Ka‐Kit Leung, Liyang Zhang

Advanced Science· Volume 13· Issue 5
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Abstract

Abstract Non‐small cell lung cancer (NSCLC) is the leading cause of brain metastases (BMs) and is characterized by a poor prognosis and limited response to standard treatments. Multi‐omics sequencings, integrating spatial transcriptomics, metabolomics, single‐cell 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‐NSCLC) and Queen Mary Hospital NSCLC (QMH‐NSCLC) cohorts. This investigation identified LOX + Malig‐5 cells as metastasis‐initiating 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‐KRT10 signaling axis that mediates the interaction between NET‐releasing neutrophils and LOX + Malig‐5 cells is discovered, thereby promoting epithelial–mesenchymal 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‐driven prediction model and in vitro/in vivo assays, fatty acid synthase inhibitor TVB‐2640 is identified as a potential therapeutic agent for disrupting metabolic vulnerability and suppressing NSCLC BMs. These findings provide novel insights into NET‐dependent cellular interactions that sustain the pro‐metastatic microenvironment underlying NSCLC BMs, offering robust development of novel metabolism‐based therapeutic strategies to combat this lethal complication.
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Research context

OpenAlex topics: Neutrophil, Myeloperoxidase and Oxidative Mechanisms · Immune cells in cancer · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurosurgery Xiangya Hospital Central South University 87 Xiangya Road Changsha Hunan 410008 China

Department of Surgery School of Clinical Medicine LKS Faculty of Medicine The University of Hong Kong Queen Mary Hospital Hong Kong SAR China

Hypothalamic Pituitary Research Center Xiangya Second Hospital Central South University 87 Xiangya Road Changsha Hunan 410008 China

National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan China

Department of Thoracic Surgery Xiangya Hospital Central South University 87 Xiangya Road Changsha Hunan 410008 China

Department of Clinical Oncology School of Clinical Medicine LKS Faculty of Medicine The University of Hong Kong Queen Mary Hospital Hong Kong SAR China

The State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐Sen University 54 Xianlie South Rd Guangzhou 510060 China

Department of Respiratory Medicine Hunan Provincial People's Hospital (The First‐Affiliated Hospital of Hunan Normal University) 61 Jiefang Xi Road Changsha Hunan 410005 China

Department of Radiology Xiangya Hospital Central South University 87 Xiangya Road Changsha Hunan 410008 China

Department of Pathology Xiangya Hospital Central South University 87 Xiangya Road Changsha Hunan 410008 China

Department of Neurosurgery National Regional Center for Neurological Diseases Xiangya Hospital (Jiangxi) Central South University Nanchang Jiangxi 330038 China

The State Key Laboratory of Brain and Cognitive Sciences The University of Hong Kong Hong Kong SAR China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Hunan Province · Science Fund for Distinguished Young Scholars of Hunan Province · Innovative Research Group Project of the National Natural Science Foundation of China

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