Abstract
Lung adenocarcinoma (LUAD)-derived leptomeningeal metastases (LM) represent a predominant subtype among all LM cases. Nevertheless, the cerebrospinal fluid (CSF) profile of LUAD-LM patients remains poorly characterized and reliable CSF diagnostic biomarkers for LUAD-LM have yet to be established. Using single-cell RNA sequencing data of CSF cells from six LUAD-LM patients, we drew a systematic transcriptomic atlas of the CSF cellular landscape. Our analysis revealed that LUAD-LM reprograms CSF into an immunosuppressive state, marked by the emergence of pro-tumoral LGMN-SELENOPhigh macrophages and proliferating CSF circulating tumor cells (CSF-CTC). Cell-cell communication analysis showed that CSF-CTC reinforces immunosuppression by co-inhibitory checkpoint axis NECTIN2_TIGIT axis with the CD8+T/NK cells, and via CD47_SIRPA axis with antigen-presenting cells. Furthermore, we identified the single-cell transcriptomic difference between CSF-CTC and tumor cells of parenchymal brain metastases (PBM). Notably, Trophoblast cell surface antigen 2 (TROP2) levels in CSF were significantly elevated in LUAD-LM patients versus both normal controls (NC) and LUAD patients without LM (Non-LM). It showed strong diagnostic accuracy for distinguishing LUAD LM from Non-LM or NC, and PBM did not influence the CSF TROP2 level. Collectively, our findings advance the understanding of LUAD-LM pathogenesis and highlight the potential of CSF TROP2 as a diagnostic biomarker for LM.
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Data availability
The data that support the findings of this study are openly available in the National Center for Biotechnology information Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE276139), reference number GSE276139.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China, grant number 82102489 (Haoyu Ruan), 82202610 (Yuexinzi Jin), 82502175 (Ting Wang), 82272429 (Ming Guan), 82103328 (Yuqing Wu), and the Shanghai Sailing Program (23YF1457700, Zhe Wang).
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H.R., M.G., Q.O., and Y.W. contributed to the conceptualization and design of the study. H.R., Z.W., J.L. (Jie Luo), Y.J., and T.W. carried out the primary coding, data analysis, and visualization. H.R. and Z.W. drafted the manuscript and assisted with the final revision of the manuscript. Y.M., J.L. (Jingping Liu), and H.J. collected the samples. All authors reviewed, provided feedback, and approved the final manuscript.
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Wang, Z., Luo, J., Jin, Y. et al. Cellular landscape and diagnostic value of TROP2 in cerebrospinal fluid of lung adenocarcinoma leptomeningeal metastases. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01379-0
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DOI: https://doi.org/10.1038/s41698-026-01379-0
