TMIC-44. Fibroblast reprogramming and immune evasion define the tumor niche in brain metastases

Abstract Brain metastases (BM) from lung adenocarcinoma represent a formidable clinical challenge due to limited therapeutic efficacy. To gain insight into complex tumor microenvironment (TME) of BM, we analyzed single-cell RNA-sequencing data comprising 66,769 cells from primary tumors (PTs; 44,355 cells) and matched BM lesions (22,414 cells). Our analysis revealed a profound shift in cellular composition during metastasis: while T cells predominated PT (44.12%), tumor cells became the most abundant population in BM (55.17%), with corresponding reductions in T cells (27.57%) and macrophages (19.3%). Cell–cell communication analysis identified fibroblasts as central mediators in both PT and BM, with a transition from collagen signaling in PT to thrombospondin signaling in BM, facilitating interactions with tumor cells, B cells, and oligodendrocytes. Ingenuity Pathway Analysis revealed enrichment of collagen-related genes in fibroblasts (MFAP4, COL15A1, FBLN1, FBLN2) and Th1/Th2 pathway genes in T cells (IKZF1, SH2D1A, RASGRP1, SKAP1). Subclustering uncovered seven distinct fibroblasts subpopulations and a notable shift from PT-enriched C0 to BM-enriched C1, suggesting dynamic phenotypic adaptation. Pseudotime trajectory analysis further clarified fibroblasts differentiation states. T-cell subclustering revealed a significant increase in immunosuppressive regulatory T cells (84.1%) and proliferating CD4+ T cells (10.5%) in BM, highlighting mechanisms of immune evasion. COL15A1 expression correlated with poor patient survival and emerged as a promising therapeutic candidate, showing increased sensitivity to Dabrafenib, Trametinib, Piperlongumine, Cabozantinib, Staurosporine, and Vemurafenib. Additional gene drug associations were observed, with FBLN1, RASGRP1, MFAP4, SH2D1A, and IKZF1 linked to potential sensitivity to Erlotinib, Afatinib, Fluorouracil, and Brefeldin A. These findings provide a high-resolution map of the BM TME and highlight COL15A1 and related pathways as potential targets for precision therapy in patients with BM.