Cellular senescence is a hallmark of cancer and induces senescence-associated inflammatory responses in the tumor microenvironment (TME). CDKN1A, an important cellular senescence marker, plays significant roles in cell proliferation, invasion, migration, and apoptosis. Previous studies have implied its drug resistance role in certain cancer types. However, its impact on immunotherapy efficacy in advanced LUAD remains unclear. Using TCGA and SU2C-MARK cohorts, we investigated CDKN1A's biological features in advanced LUAD, analyzing pathway regulation, immune infiltration, and immunotherapy associations. Single-cell RNA sequencing (GSE148071) validated TME and cellular communication differences between CDKN1A high/low expressing tumors in advanced LUAD. CDKN1A expression was positively associated with immunosuppressive environment including extracellular matrix, cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs) in advanced LUAD for both TCGA and SU2C-MARK cohorts (P < 0.05). CDKN1A showed significantly positive correlations with many senescence genes in advanced LUAD (P < 0.05), which were also positively associated with endothelial cells, epithelial cells, fibroblast cells and macrophages, but negatively associated with immune cells (P < 0.05). In multivariable cox regression, patients with high CDKN1A expression had worse OS (HR = 2.74, 95% CI = 1.31-5.73, P = 0.007) and PFS (HR = 1.78, 95% CI = 1.01-3.11, P = 0.045) than those with low CDKN1A expression when treated with immunotherapy. In contrast, the high CDKN1A expression was not associated with PFS and OS in the TCGA cohort, in which the LUAD patients received standard chemotherapy, suggesting the immunotherapy predictive role instead prognostic role of CDKN1A. Moreover, single-cell analysis revealed that CDKN1A highly expressed tumors were accompanied by an enrichment of stromal and endothelial cells within the tumor microenvironment, along with enhanced activity of SMAD3/4, the downstream transcription factors of TGFB signaling. These tumors exhibited increased cell-cell communication with stromal cells (COL1A1/COL1A2-ITGA1/ITGB1/SDC1) and endothelial cells (NAMPT-ITGAS/ITGB1/INSR). CDKN1A expression was associated with cellular senescence, immunosuppressive environment and exhibited resistance to immunotherapy in advanced LUAD, suggesting a potential combination strategy with senolytic or senomorphic therapies to overcome immunotherapeutic resistance in the future.© 2025. The Author(s).