Comprehensive analysis of diverse cytokine patterns in the prognosis and tumor microenvironment of lung adenocarcinoma

The aim of this study was to elucidate the comprehensive roles of cytokines in lung adenocarcinoma (LUAD). Cytokine-related genes were analyzed in LUAD using sequencing datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Gene Set Variation Analysis (GSVA) was employed to quantify enrichment of four cytokine families—interferons (IFNs), tumor necrosis factors (TNFs), interleukins (ILs), and chemokines (CKs)—across samples. Differential expression and survival analyses assessed the impact of each family on LUAD prognosis. A prognostic model based on TNF family genes was constructed using the least absolute shrinkage and selection operator (LASSO) regression. Functional enrichment of the TNF Score (TNFS) was performed with ClusterProfiler. Finally, the role of the key gene TNFRSF11A was validated by small interfering RNA (siRNA) knockdown, followed by Transwell migration, colony formation, and wound-healing assays. Integrated expression and survival analyses identified the TNF family as a critical regulator in LUAD. TNF scores were significantly elevated in tumor versus normal tissues, whereas CK enrichment predicted improved survival and high TNF enrichment predicted poorer survival. Differential profiling in TCGA and GEO cohorts revealed five overexpressed TNF genes—TNFRSF11A, TNFRSF13B, TNFRSF17, TNFSF13, and TNFSF11—correlated with adverse outcomes. A five-gene LASSO-derived risk model demonstrated strong prognostic performance for overall, disease-free, disease-specific, and progression-free survival. High TNFS was associated with dysregulation of cell-cycle, adhesion, and cytokine signaling pathways, as well as altered infiltration of T cells, B cells, and macrophages. Single-cell analysis further revealed that malignant cells with high TNFRSF11A expression exhibited significantly enhanced intercellular communication with fibroblasts and CD8 + T cells, characterized by the activation of specific signaling pathways. TNFRSF11A emerged as the top contributor, with expression positively correlated with smoking history, advanced TNM stage, and recurrence. Functional assays confirmed that TNFRSF11A knockdown significantly impaired LUAD cell proliferation, migration, and invasion. The TNF cytokine family plays a pivotal role in LUAD. TNFRSF11A, previously unstudied in this context, represents a novel key driver of LUAD progression.