Cellular landscape and diagnostic value of TROP2 in cerebrospinal fluid of lung adenocarcinoma leptomeningeal metastases

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-SELENOP^high 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.