Spatial Omics Profiling of Treatment-Naïve Lung Adenocarcinoma with Brain Metastasis as the Initial Presentation.

Background/objectives: Brain metastasis (BM) is a common and often early manifestation in lung adenocarcinoma (LUAD), yet its tumor microenvironment remains poorly defined at the time of initial diagnosis. This study aims to characterize early immune microenvironmental alterations in synchronous BM using spatial proteomic profiling.

Methods: We performed digital spatial proteomic profiling using the NanoString GeoMx platform on formalin-fixed paraffin-embedded tissues from five treatment-naïve LUAD patients in whom BM was the initial presenting lesion. Paired primary lung and brain metastatic samples were analyzed across tumor and stromal compartments using 68 immune- and tumor-related protein markers.

Results: Spatial profiling revealed distinct expression patterns between primary tumors and brain metastases. Immune regulatory proteins-including IDO-1, PD-1, PD-L1, STAT3, PTEN, and CD44-were significantly reduced in brain metastases ( < 0.01), whereas pS6, a marker of activation-induced T-cell death, was significantly upregulated ( < 0.01). These alterations were observed in both tumor and stromal regions, suggesting a more immunosuppressive and apoptotic microenvironment in brain lesions.

Conclusions: This study provides one of the first spatially resolved proteomic characterizations of synchronous BM at initial LUAD diagnosis. Our findings highlight early immune escape mechanisms and suggest the need for site-specific immunotherapeutic strategies in patients with brain metastasis.