肺腺癌等固体肿瘤不仅包括肿瘤细胞本身，还包括肿瘤细胞持续与相互作用的肿瘤微环境。对肺腺癌和脑转移瘤的肿瘤学特征和肿瘤微环境（TME）进行单细胞水平的深入理解，能为肺腺癌脑转移瘤提供新的治疗策略。为了解决这个问题，我们对15例肺腺癌样本和10例脑转移样本进行了单细胞RNA测序（scRNA-seq）分析。共获得86,282个单细胞，并分为8个细胞类型，包括上皮细胞、内皮细胞、纤维母细胞、少突胶质细胞、T/NK细胞、B细胞、肥大细胞和巨噬细胞。在脑转移瘤中，我们发现T/NK细胞和肥大细胞的比例显著较低，免疫调节严重紊乱。此外，我们在脑转移组织中发现一亚群高表达转移促进相关基因的巨噬细胞。此外，在脑转移瘤中，我们发现肌成纤维细胞癌相关纤维母细胞（myCAFs）的比例显著增加，内皮细胞的血管生成能力更高。脑转移瘤的上皮细胞更具恶性并经历了基因重编程。接下来，我们发现DNA损伤诱导转录因子4（DDIT4）在脑转移瘤的上皮细胞中上调表达，与预后不良相关。最后，我们通过实验证实DDIT4的下调抑制了肺癌细胞的增殖、迁移和侵袭能力。本研究通过scRNA-seq描绘了肺腺癌和脑转移瘤的单细胞图谱，并为发展肺癌脑转移瘤的未来治疗靶点铺平了道路。© 2023. Springer Science+Business Media, LLC.

Solid tumors such as lung adenocarcinoma include not only the tumor cells but also the microenvironment in which the tumor cells continuously interact with each other. An in-depth understanding of the oncological features and tumor microenvironment (TME) of lung adenocarcinoma and brain metastases at the single-cell level could provide new therapeutic strategies for brain metastases from lung adenocarcinoma.To solve this problem, we performed single-cell RNA sequencing (scRNA-seq) analysis on 15 lung adenocarcinoma samples and 10 brain metastasis samples.A total of 86,282 single cells were obtained and divided into 8 cell types, including epithelial cells, endothelial cells, fibroblasts, oligodendrocytes, T/NK cells, B cells, mast cells, and macrophages. In brain metastases, we found a significantly lower proportion of T/NK cells and mast cells, and more severe immune dysregulation. In addition, we found a subpopulation of macrophages with high expression of metastasis-promoting-related genes enriched in brain metastatic tissues. Moreover, in brain metastases, we found a significantly increased proportion of myofibroblastic cancer-associated fibroblasts (myCAFs) and a higher angiogenic capacity of endothelial cells. Epithelial cells in brain metastases were more malignant and underwent genomic reprogramming. Next, we found that DNA damage-inducible transcript 4 (DDIT4) expression was upregulated in epithelial cells in brain metastases and was associated with poor prognosis. Finally, we experimentally validated that the downregulation of DDIT4 inhibited the proliferation, migration, and invasion of lung cancer cells.This study depicts a single-cell atlas of lung adenocarcinoma and brain metastases by scRNA-seq and paves the way for the development of future therapeutic targets for brain metastases from lung cancer.© 2023. Springer Science+Business Media, LLC.