Single-cell transcriptomic analysis reveals the evolution of the immunosuppressive landscape from primary tumors to brain metastasis in LUAD

Brain metastasis (BM) is a major cause of mortality in lung adenocarcinoma, yet the cellular and molecular basis of its immune microenvironment remodeling remains unclear. Here, we systematically analyzed primary lung adenocarcinoma (LUAD) and BM samples using single-cell RNA sequencing (scRNA-seq). CD74 ^High tumor-associated macrophages (TAMs) emerged as central receptor hubs, particularly within the APP–CD74 and MIF–CD74 axes. In the TCGA cohort, high CD74 expression correlated with suppressed phagocytosis-related gene sets and poor prognosis. Comparative analysis revealed strong transcriptional similarity between BM_Cluster_03 and LUAD_TAM_Cluster_15, both serving as dominant APP–CD74 receptor populations. Stratification by CD74 expression showed that CD74 ^High TAMs in LUAD were enriched in antigen presentation, phagocytosis, and adaptive immune pathways, whereas CD74 ^High TAMs in BM shifted toward metabolic adaptation and stress responses with reduced immune effector programs. This functional reprogramming was consistently observed across analyses, indicating that BM CD74 ^High TAMs transition from an immune-activated to a metabolically stressed state, thereby facilitating immunosuppressive remodeling and tumor colonization in the brain. Collectively, CD74 ^High TAMs represent key drivers of immune remodeling in lung adenocarcinoma brain metastasis, and the APP–CD74/MIF–CD74 axes may serve as potential therapeutic targets.