The cerebrospinal fluid immune microenvironment in lung cancer leptomeningeal metastasis: cellular ecosystems and therapeutic possibilities

Leptomeningeal metastasis (LM) is a devastating form of central nervous system (CNS) dissemination in lung cancer, particularly non-small cell lung cancer (NSCLC). Current treatment frameworks emphasize CNS drug penetration, oncogenic driver evolution, and intrathecal therapy. Emerging evidence supports viewing the cerebrospinal fluid (CSF) compartment as an active tumor-immune space, but the field remains early, with limited lung cancer-specific mechanistic and single-cell datasets. Lung cancer cells in CSF appear to adapt to low protein content, limited nutrients, fluid shear, weak matrix support, and compartmental immune surveillance. Meanwhile, available CSF studies suggest immune states marked by exhausted T cells, regulatory lymphoid programs, suppressive myeloid remodeling, cytokine dysregulation, and tumor-supportive signaling. This review summarizes the CSF metastatic niche, tumor adaptation, immune-cell states, tumor-immune crosstalk, therapy-associated remodeling, and CSF multi-omics in lung cancer LM. We propose that CSF-guided profiling may help generate immune-state classifications and inform future targeted, intrathecal, immune, or combination strategies, while requiring prospective validation before routine treatment guidance.