Loss of PTEN as an Independent Poor Prognosis Indicator in Lung Adenocarcinoma, but Not in Squamous Cell Carcinoma, Is Associated with an Immunosuppressive Tumor Microenvironment and Distinct Co-Mutational Profiles

Background/Objectives: Non-small cell lung cancer (NSCLC) comprises biologically heterogeneous tumors, primarily lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which differ in genomic landscape and clinical behavior. The tumor suppressor PTEN is a key negative regulator of the PI3K/AKT/mTOR pathway and is frequently inactivated in NSCLC through genetic and non-genetic mechanisms. Although reduced PTEN expression has been associated with poor outcomes in lung cancer, its prognostic relevance across these histological subtypes remains unclear. Methods: Here, we investigated the prognostic significance of PTEN in NSCLC subtypes using a multi-level approach combining protein, transcriptomic, and genomic analyses. PTEN protein expression was evaluated by immunohistochemistry in a tissue microarray from resected NSCLC patients, and findings were validated using publicly available datasets including TCGA-RPPA, GEO/EGA-based transcriptomic cohorts, and large genomic resources. In parallel, mutational landscapes and co-mutation patterns were analyzed in several independent datasets, and tumor immune microenvironment composition was inferred using CIBERSORT deconvolution analysis. Results: Low PTEN protein and mRNA levels, as well as PTEN mutations, were consistently associated with significantly worse overall survival (OS) in LUAD but not in LUSC. Multivariable Cox regression analysis confirmed PTEN as an independent prognostic factor in LUAD. Although PTEN mutations were more frequent in LUSC, they showed no prognostic value in this subtype. Co-mutation analyses revealed recurrent PTEN partnerships with TP53, EGFR, and APC in LUAD, with PTEN-TP53 co-alterations enriched in metastatic disease. Immune deconvolution demonstrated that PTEN-low LUAD tumors were characterized by an immunosuppressive microenvironment, including increased T regulatory cells and reduced inflammatory immune populations. Notably, increased M2-like macrophages were associated with shorter OS in PTEN-low LUADs, whereas a high number of total macrophages (CD68+ cells) emerged as an independent predictor of more favorable OS. Conclusions: Collectively, these results identify PTEN loss as a subtype-specific prognostic biomarker in LUAD and link its deficiency to immunosuppressive tumor microenvironment remodeling.