Integrative single-cell and spatial transcriptomics analysis reveals MDK-NCL pathway’s role in shaping the immunosuppressive environment of lung adenocarcinoma

作者：Yu Fu, Song Li, Yikang Zhao, Xiran Zhang, Xiaolu Mao, Ran Xu · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1546382 · 被引用次数：20 · 研究领域：Single-cell and spatial transcriptomics、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

Objectives: The tumor microenvironment (TME) plays a critical role in the progression of lung adenocarcinoma (LUAD). This study aims to investigate the cellular composition of the TME in LUAD and assess the role of the MDK-NCL signaling pathway. Methods: We employed a multi-omics strategy to investigate LUAD, combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk RNA-seq datasets. Publicly available scRNA-seq data and ST data were utilized. scRNA-seq data underwent quality control, dimensionality reduction, and clustering to characterize cell populations and identify malignant epithelial subtypes using the Seurat and inferCNV packages. Spatial transcriptomics data facilitated the identification of distinct tumor niches, while immune infiltration and ligand-receptor interactions were analyzed using MCPcounter and Niches. Experimental validation was performed via real-time PCR and western blotting on paired LUAD and adjacent normal tissue samples. Results: scRNA-seq revealed the presence of multiple immune and stromal cell populations, with malignant epithelial cells being subdivided into six clusters. The MDK-NCL axis demonstrated high activity in malignant cells, showing strong interactions with immune and stromal components. Spatial transcriptomics revealed nine distinct tumor niches, with MDK-NCL signaling notably upregulated at the tumor-immune interface, highlighting its role in establishing an immunosuppressive microenvironment. In both ...