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 (p< 0.01), whereas pS6, a marker of activation-induced T-cell death, was significantly upregulated (p< 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.
背景/目的：脑转移是肺腺癌常见且常为早期表现，但在初诊时其肿瘤微环境特征仍不明确。本研究旨在通过空间蛋白质组学分析，揭示同步性脑转移的早期免疫微环境改变。方法：我们采用NanoString GeoMx平台对五例以脑转移为首发症状的初治肺腺癌患者的福尔马林固定石蜡包埋组织进行数字空间蛋白质组学分析。使用68种免疫及肿瘤相关蛋白标志物，对配对的原发性肺肿瘤和脑转移样本的肿瘤区与基质区进行比较。结果：空间分析显示原发肿瘤与脑转移灶之间存在显著表达差异。脑转移灶中免疫调节蛋白（包括IDO-1、PD-1、PD-L1、STAT3、PTEN和CD44）表达显著降低（p<0.01），而激活诱导T细胞死亡标志物pS6则显著上调（p<0.01）。这些改变在肿瘤区和基质区均有体现，提示脑转移病灶存在更具免疫抑制和细胞凋亡倾向的微环境。结论：本研究首次在肺腺癌初诊阶段对同步性脑转移进行了空间分辨蛋白质组学表征。研究结果揭示了早期免疫逃逸机制，提示脑转移患者可能需要针对病灶部位的特异性免疫治疗策略。
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