Single-Cell Dissection of Inflammatory Suppression and Stemness Plasticity Reveals STMN1-Associated Malignant...

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.