免疫疗法在胸膜间皮瘤（PM）中显示出巨大的前景，但大多数患者仍未达到显着的临床反应，这凸显了提高对肿瘤微环境（TME）了解的重要性。在这里，我们利用高通量、单细胞 RNA 测序从头鉴定 54 个表达程序并构建了 PM TME 的综合细胞目录。我们发现了四种与不良疾病结果相关的癌症内在程序，以及一种可能对 VEGF 信号反应并促进血管生成的新型胎儿样内皮细胞群。在整个细胞区室中，我们观察到与癌症固有肉瘤样特征相关的 TME 存在显着差异，包括胎儿样内皮细胞、CXCL9 巨噬细胞、细胞毒性 T 细胞、耗尽 T 细胞和调节性 T 细胞的富集，我们使用成像和批量反卷积分析对其进行了验证关于独立队列。最后，我们通过计算和实验证明，NK 细胞和肿瘤细胞之间的 NKG2A-HLA-E 相互作用代表了 PM 的重要新治疗轴，特别是对于上皮样病例。

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.