肿瘤微环境（TME）对于肾细胞癌（RCC）等癌症的进展和治疗反应具有贡献。之前的概况研究，包括单细胞转录组学，通常样本量有限且缺乏空间定位。脑转移性RCC的TME，作为主要死亡原因，也仍然缺乏详细描述。我们在NanoString GeoMx平台上进行了数字空间分析，在代表RCC进展阶段的组织芯片上使用了52个经过验证的免疫肿瘤学标记。我们对76个原发肿瘤，27个附近组织的肾样本和86个转移灶进行了概况分析，其中包括24个脑转移灶。我们观察到两个不同队列中，转移灶与原发肿瘤相比，免疫检查点（TIM-3和CTLA-4），细胞毒性（GZMA和GZMB）和T细胞活化（CD25）蛋白表达水平较低。我们还发现转移灶中巨噬细胞发生了变化，易感脑转移的患者在转移样本中显示出较少的M1型炎症巨噬细胞标记物（HLA-DR和CD127）。与颅外转移病灶相比，脑转移病灶中表达抗凋亡BCL-2家族蛋白BCL-XL较高，而天然免疫激活物STING的表达较低。脑转移TME中较低的TIM-3和CD40与较长的生存期相关，这一发现需要进一步验证。与原发肿瘤相比，RCC转移，包括脑转移，表达了多种免疫激活标记物和现有或正在研究的治疗靶点的表达水平较低。我们的发现对设计未来的生物标志物和治疗研究可能具有重要意义，并可能有助于脑转移特异性疗法的发展。 © 作者（或其雇主）2023年。根据CC BY-NC许可进行再利用。未经商业使用。请查看权利和权限。由BMJ出版。

The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized.We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases.We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation.Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.