背景：肺癌与高死亡率相关，并且常合并恶性胸腔积液（MPE），该疾病预后差，患者寿命短暂。然而，我们对胸腔转移病理生物学的细胞特异性机制仍了解不完全。方法：我们分析了患者肺癌和充血性心力衰竭（作为对照）搜集的胸腔积液中细胞的单细胞转录组。使用多肽细胞因子珠子法测量可溶性和补体因子。通过GPX4小干扰RNA（siRNA）转染和过表达评估了铁死亡的作用。结果：我们发现胸膜间皮细胞的间皮-间质转变（MesoMT）导致胸腔转移，肺癌/胸膜细胞共培养实验证实了这一点。防止癌细胞因细胞外基质脱离二次性死亡的铁死亡耐受对胸腔转移至关重要。我们发现在肺癌患者的MPE中存在着免疫抑制的脂质相关的肿瘤相关巨噬细胞（LA-TAMs），并且具有补体级联改变。特别是在MPE中还发现了上调的补体因子，并且C5与表皮生长因子受体突变的肺癌患者的总生存率负相关。浆细胞样树突状细胞（pDCs）表现出功能失调的表型和促肿瘤特征。从pDCs中提取的基因集的高表达与肺癌患者的不良预后相关。受体-配体相互作用分析揭示了胸腔转移巢通过间皮细胞-癌细胞/免疫细胞之间通过TNC和ICAM1的相互作用加剧。结论：总之，我们的结果突出了涉及肺癌胸腔转移病理生物学发展的细胞特异性机制。这些结果对胸腔微环境进行了大规模和高维度的表征，并为肺癌的治疗药物未来的发展提供了有用的资源。© 作者

Background: Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete. Methods: We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by GPX4 small interfering RNA (siRNA) transfection and overexpression. Results: We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via TNC and ICAM1. Conclusions: Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.© The author(s).