Single-cell combined with bulk transcriptomics reveals cross-cancer common regulatory mechanisms in the brain metastasis microenvironment and the clinical significance of the MIF-CD74 axis

Brain metastases (BrMs) cause high mortality in advanced solid tumors with variable incidence, and 5-year survival remains less than 10% due to heterogeneous tumor microenvironments (TME). Key questions about cross-cancer TME regulatory mechanisms and tumor transcriptional adaptation to the brain remain understudied. We integrated single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics to analyze 4 BrM samples, using Seurat for TME cellular composition, multiNMF for conserved meta-programs (MPs), and CellChat for intercellular networks, with GSE186344 for validation. We identified 7 core cell types, and stromal cells formed shared clusters (cross-cancer TME commonalities). Six MPs were found. MP3 (stress response) and MP5 (development-related) were linked to longer survival, and MP6 (epithelial–mesenchymal transition, EMT) was positively correlated with MP3 and MP2 (immune) ( r = 0.63). Macrophage migration inhibitory factor (MIF)-(CD74+CXCR4) was the core tumor-myeloid cell interaction hub (especially with plasmacytoid dendritic cells, pDCs), and high pDC signature gene expression correlated with shorter survival ( p = 0.039). This framework supports the MIF-CD74 axis as a therapeutic target, requiring further validation.