Search Results (736)

Background: Spread through air spaces (STAS) is a recognized histologic pattern of invasion associated with poor prognosis in non-small-cell lung cancer (NSCLC), particularly adenocarcinoma. However, its presence in pulmonary squamous cell carcinoma (SCC), whether primary or metastatic, remains largely unexplored. Given the limited available evidence, this study was designed as an exploratory analysis to evaluate the prevalence and potential prognostic significance of STAS in pulmonary SCC. Material and Methods: In this exploratory retrospective study, we analyzed 57 patients who underwent surgical resection for pulmonary squamous cell carcinoma (P-SCC) at the Department of Thoracic Surgery at the University Hospital Erlangen between 2008 and 2020. The cohort included both primary lung SCC and metastatic SCC to the lung from extrapulmonary sites, primarily from ear, nose, and throat (ENT) tumors. Histological slides were reviewed to assess the presence of STAS, as defined by established morphological criteria. The Chi-square test was used to investigate the presence of STAS. Disease-free survival (DFS) and overall survival (OS) was evaluated using Kaplan–Meier analysis, and the prognostic impact of STAS along other variables were assessed using Cox proportional hazards regression. Results: A total of 57 patients with squamous cell carcinoma (SCC), 22 (39%) had primary lung SCC and 35 (61%) had metastatic SCC from head and neck tumours (ENT). Spread through air spaces (STAS) was detected in 20 patients (35%). Disease-free survival (DFS) differed according to primary tumour location (p-value of 0.009), with higher 1-, 3-, and 5-year DFS in patients with primary lung SCC (86.4%, 77.3%, 63.3%) than in those with head and neck SCC (54.3%, 31.4%, 22.2%). DFS was also significantly higher in patients undergoing solitary resections compared with multiple resections (78.6%, 64.3%, 49.5% vs. 33.3%, 6.7%, not estimable; p-value < 0.001). DFS was slightly longer in STAS-negative patients compared with STAS-positive patients (1-, 3-, 5-year DFS: 64.9%, 51.4%, 40.5% vs. 70%, 45%, not estimable), (median DFS 36 vs. 25 months; p-value of 0.776). Overall survival (OS) was significantly longer in patients with primary lung SCC (median OS 125 months) than in those with head and neck SCC (27 months; p-value of 0.039). STAS-negative patients had also a longer OS than STAS-positive patients (median OS 46 vs. 38 months; HR = 1.11, 95% CI 0.56–2.20; p-value of 0.771). Conclusions: STAS was identified in metastatic pulmonary SCC lesions as well as in primary lung SCC, occurring in approximately one-third of cases. However, due to the limited cohort size and the exploratory univariate design of the study, the prognostic significance of STAS could not be definitively established and requires further investigation in larger, adequately powered studies. Full article

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains the leading cause of cancer mortality worldwide. While immune checkpoint inhibitors (ICIs) have revolutionized treatment, primary and acquired resistance, and immune-related adverse events (irAEs) limit their therapeutic efficacy. Recent evidence highlights the gut and local microbial communities as a modifiable determinant of NSCLC outcomes, especially in the context of ICI use. Emerging data support the concept of a gut–lung-immune axis, a tridirectional communication pathway, in which gut and lung microbial communities influence local and systemic antitumor immunity through immune cell trafficking, cytokine signaling, and microbial-derived metabolites. In this review, we synthesize current clinical and mechanistic studies examining the role of gut, tumor-resident, and circulating microbiota in shaping ICI efficacy and toxicity in NSCLC. Distinct gut and tumor microbial signatures, such as the abundance of Akkermansia muciniphila and Bifidobacterium, correlate with improved ICI response, whereas dysbiosis promotes immune suppression, resistance, and irAEs. Additionally, we highlight emerging microbial-based biomarkers, including fecal microbial profiles, circulating microbial DNA, and composite tools such as TOPOSCORE, which show promise for predicting response, toxicity, and optimal treatment duration. Overall, these findings underscore the gut–lung-immune axis as a key regulator of immunotherapy outcomes in NSCLC and suggest that microbiome-informed strategies may enable more precise, effective, and safer personalization of ICI therapy. Full article

Cathepsin C (CTSC), also known as dipeptidyl peptidase I, is an upstream activator of serine protease networks that may promote metastatic progression through inflammatory amplification and microenvironmental remodeling. Increasing evidence suggests that CTSC contributes to cancer progression not simply as an overexpressed lysosomal protease, but as a context-dependent regulator of metastatic traits. This review summarizes the structure, maturation, and biological functions of CTSC, with emphasis on its protease-activating capacity and its links to tumor-associated inflammation. Current evidence connecting CTSC to epithelial–mesenchymal transition, extracellular matrix remodeling, neutrophil extracellular trap formation, and immune microenvironment reprogramming is then synthesized across hepatocellular carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, non-small-cell lung cancer, and glioma. Available data most strongly support a pro-metastatic role for CTSC in breast cancer and colorectal cancer, whereas evidence in several other malignancies remains predominantly preclinical and mechanistically incomplete. Importantly, CTSC is better viewed as a targetable protease network hub than as a universal pan-cancer metastatic driver. The biomarker potential and therapeutic relevance of CTSC are also evaluated, with particular attention to the opportunities and limitations of current DPP-1/CTSC inhibitors and the need for tumor-specific translational strategies. Overall, CTSC represents a promising but still incompletely validated target in oncology, and future work should prioritize tissue-specific dependency, biomarker qualification, and rational combination approaches. Full article

Background: Prognostic stratification remains challenging in patients with stage IIIC non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy (CCRT), and the relative performance of host-related prognostic indices in this setting is unclear. The CARWL (C-reactive Protein, Albumin, and Recent Weight Loss) score and the Naples prognostic score (NPS) have each been proposed as prognostic tools, but direct comparisons are lacking. This study compared their prognostic performance. Methods: We retrospectively analyzed 795 patients with stage IIIC NSCLC treated with CCRT between 2010 and 2020. Patients were stratified into three prognostic groups according to CARWL and NPS. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and locoregional PFS (LRPFS) were secondary endpoints. Survival was assessed using Kaplan–Meier analysis and Cox regression. Results: Both CARWL and NPS significantly stratified OS, PFS, and LRPFS (all p < 0.001). CARWL demonstrated modestly higher discriminatory performance across endpoints. The OS difference between unfavorable and favorable groups was larger with CARWL than with NPS (19.3 vs. 12.3 months). CARWL also provided greater separation for PFS (5.3 vs. 3.2 months) and LRPFS (4.9 vs. 3.4 months). In multivariable analyses, both indices retained independent prognostic significance; however, CARWL consistently exhibited stronger hazard gradients and maintained prognostic value when modeled alongside NPS. Conclusions: Both CARWL and NPS offered meaningful prognostic stratification in stage IIIC NSCLC treated with CCRT, but CARWL demonstrated a modest but more consistent prognostic discrimination than NPS. Pending external validation, CARWL represents a practical and biologically grounded tool for risk stratification in this population. Full article

Background and Objectives: Surfactant protein B (SFTPB) is a surfactant-associated protein secreted by alveolar type II epithelial cells that plays a critical role in maintaining alveolar stability and surface tension. Although SFTPB is closely associated with pulmonary epithelial differentiation, its clinical significance in different non-small cell lung cancer (NSCLC) subtypes remains unclear. This study investigated the clinicopathologic and prognostic significance of SFTPB expression in lung adenocarcinoma (AD) and lung squamous cell carcinoma (SCC) using The Cancer Genome Atlas (TCGA) dataset. Materials and Methods: SFTPB mRNA expression data and clinicopathologic information were obtained from TCGA cohorts of AD and SCC patients. Patients were stratified into high- and low-expression groups according to median SFTPB expression levels. Associations between SFTPB expression and clinicopathologic variables were analyzed, and correlation analyses were performed with major oncogenic genes. Overall survival (OS) and relapse-free survival (RFS) were evaluated using Kaplan–Meier survival analysis and log-rank testing. Multivariate Cox proportional hazards regression analyses were performed after adjustment for age, sex, and pathological stage. Results: In AD, high SFTPB expression was significantly associated with lower pathologic stage (p = 0.011) and lower N stage (p = 0.006). SFTPB expression showed significant negative correlations with EGFR (R = −0.140, p = 0.002) and BRAF (R = −0.177, p < 0.001) and a positive correlation with TP53 (R = 0.128, p = 0.004). Patients with high SFTPB expression demonstrated significantly improved OS compared with those with low expression (p < 0.001), while a trend toward prolonged RFS was observed without statistical significance (p = 0.089). Multivariate analysis confirmed high SFTPB expression as an independent favorable prognostic factor in AD (HR = 0.551, 95% CI = 0.405–0.748, p < 0.001). In SCC, high SFTPB expression was also significantly associated with lower pathologic stage (p = 0.009) and lower N stage (p = 0.007). SFTPB expression showed significant negative correlations with SOX2 (R = −0.176, p < 0.001), PIK3CA (R = −0.143, p = 0.002), and TP53 (R = −0.101, p = 0.026). In contrast to AD, high SFTPB expression was significantly associated with poorer OS (p = 0.026), whereas no significant difference in RFS was observed (p = 0.307). Multivariate analysis demonstrated that high SFTPB expression was an independent adverse prognostic factor in SCC (HR = 1.347, 95% CI = 1.028–1.767, p = 0.031). Conclusions: SFTPB expression is significantly associated with clinicopathologic characteristics and molecular signatures in both AD and SCC. However, its prognostic implications differ according to histologic subtype. High SFTPB expression independently predicts favorable survival in AD but unfavorable survival in SCC, suggesting distinct lineage-specific biological roles in NSCLC. These findings support SFTPB as a subtype-specific prognostic biomarker reflecting differential differentiation states and lineage context in NSCLC. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, the limited predictive value of PD-L1 expression as a biomarker underscores the urgent need for more reliable predictors of ICI response. Interferon regulatory factor 1 (IRF1) is a transcription factor that lies downstream of interferon-γ signaling and directly regulates CD274 (PD-L1) transcription. Here, we performed a comprehensive bioinformatic analysis to identify microRNAs (miRNAs) that may be associated with IRF1 expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Using data from The Cancer Genome Atlas (TCGA), we identified 20 miRNAs whose expression levels consistently and negatively correlated with IRF1 mRNA levels in both LUAD and LUSC. Among these, only hsa-miR-301b possesses conserved binding sites in the 3′UTR of IRF1 mRNA, suggesting direct post-transcriptional repression. For the remaining 19 miRNAs, we hypothesized an indirect mechanism of action. Further analysis revealed that hsa-miR-183 and hsa-miR-141 may target the transcription factor genes NFKB1 and STAT4, respectively, both of which positively correlate with IRF1 expression and are themselves associated with improved survival in ICI-treated patients. This study delineates a multi-layer miRNA regulatory network associated with IRF1 expression in NSCLC and identifies hsa-miR-301b, hsa-miR-183 and hsa-miR-141 as candidate upstream regulators of IRF1. Direct survival analysis for these miRNAs in ICI-treated cohorts was not feasible due to the lack of publicly available miRNA-seq data with treatment annotations; therefore, their clinical predictive value remains hypothetical, and experimental validation is required to assess their potential as predictors of ICI response. Full article

Short-term mortality following the last dose of immune checkpoint inhibitors (ICIs) is an increasingly recognized real-world outcome measure, yet its clinical predictors remain poorly characterized. This multicenter retrospective study included 458 consecutive patients with advanced melanoma, non-small cell lung cancer, or renal cell carcinoma who received ICIs at four tertiary centers in Turkey between 2018 and 2023. The primary endpoint was 30-day mortality after the final ICI dose. Among 458 patients, 71 (15.5%) died within 30 days. Multivariable logistic regression identified ECOG performance status ≥ 2, number of metastatic sites ≥ 3, and log-transformed C-reactive protein-to-albumin ratio (log-CAR) as independent predictors of 30-day mortality in Model 1 (AUC 0.954), while ECOG PS ≥ 2, brain metastasis, metastatic sites ≥ 3, and log-NLR were independent predictors in Model 2 (AUC 0.912). In the lung cancer subgroup, log-CAR and NLR remained independent predictors while ECOG PS did not. Patients who died within 30 days had significantly shorter progression-free survival (1.18 vs. 4.63 months) and overall survival (2.30 vs. 14.39 months) compared with survivors. These findings suggest that routine assessment of inflammatory and nutritional biomarkers alongside tumor burden parameters may help identify patients at high risk of early mortality and inform the timing of supportive care in ICI-treated populations. Full article

Lung cancer remains the most prevalent malignancy and the leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. β-Hydroxybutyrate (BHB), the primary circulating ketone body, has shown antitumor activity in other cancers, but its role in non-small cell lung cancer (NSCLC) is not well defined. This study investigated the anticancer and anti-angiogenic effects of BHB alone and in combination with Gemcitabine using in vitro and in vivo approaches. In A549 (adenocarcinoma) and LNM35 (large-cell carcinoma) NSCLC cells, BHB significantly reduced cell number and colony growth in a concentration-dependent manner, with LNM35 cells exhibiting greater sensitivity. Migration of both A549 and LNM35 cells was also markedly inhibited. In endothelial Telo-HAEC cells, BHB exhibited no cytotoxicity but significantly inhibited migration, tube formation, and VEGF-induced spheroid sprouting, indicating anti-angiogenic activity. Combination studies showed that BHB enhanced Gemcitabine-mediated suppression of NSCLC cell number and colony growth, consistent with an additive to synergistic effect. In the chick embryo chorioallantoic membrane model, BHB and Gemcitabine reduced tumor growth individually, while their combination further decreased tumor weight, particularly in LNM35 xenografts, without observable toxicity. These findings provide preclinical evidence that BHB enhances Gemcitabine antitumor activity against NSCLC and reveals its in vitro anti-angiogenic effects. Full article

Background/Objectives: Non-small-cell lung carcinoma (NSCLC) accounts for approximately 85% of lung cancers and remains a leading cause of cancer-related mortality. Although cisplatin is a cornerstone chemotherapeutic agent, its clinical effectiveness is limited by drug resistance and systemic toxicity. Capsaicin (CAP), a bioactive phytochemical derived from chili peppers, has demonstrated anticancer activity in several tumor types and has been investigated as a potential adjunct to conventional chemotherapy. Methods: An experimental study was conducted using A549 NSCLC cells and a xenograft mouse model. Cells were treated with CAP (50–300 µM), cisplatin (1 µg/mL), or their combination. Cell proliferation and apoptosis were evaluated using sulforhodamine B (SRB) assay, immunocytochemistry, and Western blot analysis. In vivo, tumor growth inhibition, histopathological alterations, and immunohistochemical expression of Ki-67 and cleaved caspase-3 were assessed. Results: Low CAP concentrations (50–100 µM) slightly increased proliferation, whereas concentrations ≥ 150 µM significantly reduced cell viability and induced apoptosis. Cisplatin monotherapy markedly suppressed proliferation and activated apoptosis. Bliss independence analysis demonstrated concentration-dependent synergy between CAP and cisplatin, with maximal synergy scores reaching 28.1 at 100 µM CAP. Combination treatment at CAP concentrations ≥ 150 µM produced the strongest antiproliferative effect in vitro and the highest tumor growth inhibition in vivo (88%). CAP did not further enhance cisplatin-induced apoptosis but significantly reinforced proliferation suppression with reduced Ki-67 expression. Conclusions: CAP exhibits biphasic dose-dependent effects in NSCLC and enhances cisplatin antitumor efficacy predominantly through proliferation suppression, supporting its further evaluation as an adjunctive phytochemical in cisplatin-based NSCLC therapy. Full article

Many patients develop poor clinical response to immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1 blockade. However, transcriptomic features of chemokine receptors associated with poor response remain incompletely characterized. We analyzed publicly available single-cell RNA sequencing datasets from non-small-cell lung cancer (NSCLC) and melanoma cohorts, with additional exploratory analyses in hepatocellular carcinoma (HCC) and colorectal cancer datasets. Chemokine receptor expression on CD8+ T cells from clinical responsive and non-responsive samples to anti-PD-1 therapy was systematically profiled. Differential gene expression, cell-state scoring, pseudotime trajectory inference, and ligand–receptor interaction analysis were performed to characterize associated transcriptional states and predicted cellular interactions. CCR5 transcript expression in tumor-infiltrating CD8+ T cells was associated with lower responsiveness to PD-1/PD-L1 blockade therapy. CCR5+ CD8+ T cells exhibited transcriptional features associated with increased exhaustion, reduced stemness, and advanced differentiation. Pseudotime inference suggested progressively increased CCR5 expression along the inferred differentiation trajectory. Ligand–receptor interaction analysis further identified predicted interactions between CCR5+ CD8+ T cells and tumor-associated myeloid cells, with elevated expression of CCL3 and CCL4 observed in myeloid populations from non-responsive tumors. Together, these findings identify transcriptomic associations between CCR5+ CD8+ T cell states and poor clinical response to PD-1 blockade therapy. These observations support the CCL3/4–CCR5 axis as a candidate pathway for future spatial, functional, and experimental validation. Full article

Background/Objectives: Programmed death-ligand 1 (PD-L1) expression is commonly used as a predictive biomarker in metastatic non-small cell lung cancer (NSCLC); however, its clinical utility in real-world settings remains uncertain. This study evaluated the association between PD-L1 expression and treatment outcomes in patients receiving immune checkpoint inhibitors (ICIs). Methods: In this retrospective, single-center study, 86 patients with metastatic NSCLC treated with ICIs (pembrolizumab or atezolizumab) between January 2020 and December 2025 were included. PD-L1 expression was assessed using 22C3 or SP263 assays and categorized as <50% and ≥50%. The primary endpoint was time to progression (TTP), while the secondary endpoint was objective response rate (ORR). Survival analyses were performed using Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards models. Results: PD-L1 data were available for 78 of the 86 patients. The median age was 66 years (IQR 61–73); 76.7% of patients were male and 65.1% were former smokers. Adenocarcinoma was the predominant histological subtype (47.7%), followed by squamous cell carcinoma (41.9%). The ORR was similar between treatment groups (atezolizumab: 62.5%; pembrolizumab: 64.9%; p = 0.84). No statistically significant difference in TTP was observed between PD-L1 <50% and ≥50% groups. Kaplan–Meier analysis showed no statistically significant difference in TTP between PD-L1 groups (log-rank p = 0.094), although a numerical trend toward shorter TTP was observed in patients with PD-L1 ≥50%. In multivariate Cox regression analysis, PD-L1 ≥50% was not associated with TTP (hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.77–3.05; p = 0.20). No other clinical variables, including smoking status and liver metastases, were significantly associated with outcomes. Conclusions: In this limited, retrospective single-center cohort with a heterogeneous treatment mix (chemo-immunotherapy and immunotherapy monotherapy), PD-L1 expression was not significantly associated with treatment response or time to progression. While these results should be interpreted cautiously given the modest sample size and the small number of progression events, they are consistent with broader real-world evidence indicating that PD-L1 expression alone may not reliably stratify clinical benefit in metastatic NSCLC. Larger prospective studies integrating PD-L1 with complementary biomarkers are needed to confirm these observations. Full article

Background/Objectives: How the histologically benign tier of lung preinvasive lesions—atypical adenomatous hyperplasia (AAH) and squamous dysplasia (SD)—relates genomically to its paired carcinoma is unclear. To identify early versus late events, we compared synchronous preinvasive and invasive lesions from the same patient. Methods: Whole-exome sequencing was performed on 33 FFPE samples from 11 patients (7 AAH–lung adenocarcinoma [LUAD] and 4 SD–squamous cell carcinoma [SqCC] pairs, with paired normal lung). FFPE artefacts were mitigated by paired-normal subtraction, panel-of-normals filtering, and orthogonal caller cross-validation. Cancer-panel variants were classified as cancer-only, shared, or preinvasive-only. Results: Only ∼10% of cancer-panel variants were shared between paired lesions (∼50% carcinoma-only, ∼40% preinvasive-only), indicating that benign AAH/SD do not broadly mirror the paired carcinoma. Within this small shared fraction, the early-driver pattern diverged between tracks: AAH–LUAD pairs tended to share EGFR alterations, whereas the four SD–SqCC pairs featured MET-pathway alterations without any shared EGFR events. TP53 and most other canonical drivers were carcinoma-confined (within-cohort contrast direction-consistent but non-significant); three patients lacked any canonical driver despite substantial mutational burden. Conclusions: In this pilot cohort, benign AAH and SD were genomically largely distinct from their paired carcinomas, sharing only a small set of key drivers whose identity diverged between glandular and squamous tracks. This suggests that benign-appearing AAH/SD differ from the more advanced AIS/MIA precursors not only histologically but also at the genomic level. These hypothesis-generating findings require confirmation in larger, multi-omic cohorts. Full article

Background and Objectives: Positron emission tomography with 18F-FDG (PET-CT) provides a quantitative measure of tumor metabolic activity through the maximum standardized uptake value (SUVmax) of lung tumors—a measure of metabolic activity that may have prognostic value in non-small cell lung cancer (NSCLC). This study evaluated whether preoperative tumor SUVmax predicts outcomes in resected NSCLC. Materials and Methods: This single-center retrospective study included 209 consecutive patients with resected NSCLC who had preoperative FDG PET-CT. SUVmax of the primary tumor was recorded, and patients were stratified into low- and high-SUVmax groups to evaluate survival outcomes. Results: Median age was 62 years and 77% were male. Histologic subtypes were adenocarcinoma (44%), squamous carcinoma (43%), and others (13%), with stage I–III distribution of 39.7%, 33.5%, and 26.8%, respectively. SUVmax demonstrated moderate discrimination for mortality (AUC = 0.652), with an optimal cutoff of 11.14. Patients with SUVmax ≥ 11.14 had significantly worse OS and DFS. However, on multivariate analysis, SUVmax was not an independent predictor of outcomes, while extracapsular invasion (OS) and adjuvant chemotherapy (DFS) remained significant. Conclusions: In this cohort of resected NSCLC, high preoperative SUVmax (≥11.14) was associated with more advanced tumor stage and worse OS/DFS but was not an independent prognostic factor after accounting for other variables. Tumor invasiveness and use of adjuvant therapy were stronger outcome predictors. Preoperative SUVmax may help identify high-risk patients when considered alongside established clinicopathologic factors. Full article

Background: Immune-related snoRNAs remain largely uncharacterized in cancer. Methods: We comprehensively investigated their functions and clinical relevance through an integrative pan-cancer analysis of The Cancer Genome Atlas (TCGA) datasets. We systematically identified immune-related snoRNAs via partial correlation with immune pathways and GSEA, validated their functions in vitro, and performed molecular subtyping in non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSC). Results: We established a comprehensive landscape of immune-related snoRNAs associated with core immune pathways, the majority of which were dysregulated across cancers and correlated with tumor immune cell infiltration. Functional screening revealed that numerous immune-related snoRNAs were aberrantly expressed in cancer stem cells; notably, SNORD116-19 potently suppressed breast cancer stemness and metastasis. Using a panel of immune-related snoRNAs, we classified NSCLC into three molecular subtypes with distinct molecular features and immune microenvironments, suggesting divergent immunotherapy response patterns. This classification framework was successfully extrapolated to HNSC. Conclusions: Our findings suggest that immune-related snoRNAs may serve as potential regulators linking tumor progression and immunity and could be explored as candidate biomarkers for molecular subtyping with the potential to inform personalized immunotherapy strategies. Full article

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. Full article