Single‐Cell Dissection of Inflammatory Suppression and Stemness Plasticity Reveals STMN1‐Associated Malignant Epithelial Cells in Severe Lung Cancer

ABSTRACT

The disease course in patients with advanced lung cancer with malignant serous effusions (ALC‐MSE) is complex, and treatment outcomes are difficult to predict; systematic studies on the tumor stem cell‐like characteristics and regulatory mechanisms of this condition are still lacking. Based on single‐cell transcriptomic data and the TCGA‐LUAD cohort, this study systematically analyzed the functional characteristics and key regulatory networks of malignant epithelial cells in severe lung cancer. Key findings include: epithelial cells in severe lung cancer exhibit significantly attenuated inflammation‐ and immunity‐related signaling pathways (including NF‐κB, TNF, and JAK–STAT signaling pathways), enhanced stem cell‐like properties, and metabolic reprogramming; we identified a highly stem‐like malignant epithelial cell subpopulation, represented by Cluster 3, which is enriched in stem‐like pathways such as Notch, Hippo, TGF‐β, and FoxO, and is accompanied by enhanced mitochondrial metabolism and stress adaptability; STMN1 is a key molecule regulating this stem‐like state, showing a significant positive correlation with stemness scores and mRNAi; cells with high STMN1 expression gain a survival advantage and may maintain their stemness by attenuating CAF/ECM signaling with other cells (COL1A1‐CD44), inhibiting complement activation and antigen presentation signaling (such as C3, ANXA1, and MHC‐II‐related molecules), and enhancing stemness niche signaling (MIF‐CD74/CD44). Furthermore, NELFE, MYBL2, FOXN3, POLR2A, and RAD21 were identified as potential upstream regulators of STMN1. In vitro experiments confirmed that, following induction of stem cell‐like properties, STMN1 was significantly overexpressed in lung adenocarcinoma cells, accompanied by upregulation of related stem cell markers (SOX2, NANOG, OCT4, and CD44). In summary, this study reveals a significantly enhanced stemness state in malignant epithelial cells in advanced lung cancer, accompanied by suppressed inflammatory signaling and enhanced metabolic adaptation, and identifies STMN1 as a key molecule driving stemness maintenance and disease progression.