bims-meluca 2025-12-14 papers

Front Oncol. 2025 ;15 1676797

Redox phenotype confers T cell-exclusion microenvironment and resistance to immunotherapy by suppressing STING/MDA5 expression and interferon signaling in lung cancers harboring KEAP1/STK11 mutations.

Ashish Shrestha, Yangchan Li, Lixia Huang, Shaoli Li, Yanbin Zhou, Jincui Gu, Ziying Lin.

Background: KEAP1 and STK11 are frequently mutated in NSCLC, and are associated with compromised response to immunotherapy, the underlying mechanism of which is not fully understood.
Methods: To assess the impact of KEAP1/STK11 mutations on immune profiles, we analyzed RNA-seq data from the TCGA lung cancer cohort and the GSE72094 cohort. Differential expression, pathway enrichment, and correlation analyses were performed to elucidate the underlying mechanisms. Key findings were further validated using a single-cell RNA-seq dataset. Additionally, the prognostic significance of these mutations in immunotherapy was evaluated using immune checkpoint inhibitor (ICI) cohorts from our medical center and published studies.
Results: We observed the simultaneous upregulation of pathways involved in oxidoreductase activity and down-regulation of interferon signaling pathways by mutation of KEAP1 or STK11, and developed a redox signature driven by KEAP1/STK11 mutations. Redox score exhibited negative correlation with expression of STING/MDA5, which function as sensors of dsDNA/dsRNA and activate downstream interferon signaling. Redox score and STING/MDA5 expression manifested the exact opposite impact on the infiltrating level of most immune cells. Analysis of single cell RNA sequencing dataset indicated that redox phenotype specifically impacted expressional level of STING/MDA5 in cancer cells but other cell types within tumor immune microenvironment. Prognostic significance of redox signature was validated in immunotherapy cohorts of lung cancer and melanoma, which all indicated a significant worse outcome associated with higher redox score.
Conclusions: Collectively, we associated the redox status mediated by loss-function mutations of KEAP1 or STK11 to immune evasion and immunotherapeutic resistance by suppressing STING/MDA5 expression and interferon signaling of cancer cells. Our findings link redox homeostasis to STING/MDA5 expression and tumor immunogenicity, raising the possibility that targeting this axis could represent a future strategy to enhance ICI efficacy.

Keywords: KEAP1/STK11 mutations; MDA5; STING; immune microenvironment; redox phenotype

DOI: https://doi.org/10.3389/fonc.2025.1676797

J Cardiothorac Surg. 2025 Dec 09. 20(1): 456

Plasma metabolites as biomarkers for screening and differential diagnosis of lung cancer.

Zixu Liu, Ling Wang, Shugeng Gao, Qi Xue, Fengwei Tan, Yushun Gao.

BACKGROUND: Currently, there is a lack of satisfactory biomarkers for lung cancer screening and differential diagnosis. Metabolomics can detect the differences of metabolites in different pathological states, which may be helpful in the identification of lung cancer.
METHODS: Patients with pulmonary nodules were divided into two groups: benign pulmonary nodules (BPN) and primary lung cancer (PLC). Healthy population group(HPG) was enrolled. Half of PLC and HPG were selected as the testing subset and the validating subset, respectively. Two groups with different pulmonary lesions were compared with HPG, respectively, and compared with each other. Univariate and multivariate data statistical analysis method was used to select the metabolites. Their discriminating ability was verified by the ROC curve in the validating subset.
RESULTS: The testing subset was comprised of BPN(n = 32), PLC(n = 80), and HPG(n = 48). The significant metabolites selected by the comparison of PLC and HPG were 1-salicylate glucuronide, s-nitrosoglutathione, and dihydrocaffeic acid 3-O-glucuronide. Their AUC of ROC was all greater than 0.95(0.957-0.995) in the validating subset, which indicated they had a strong ability to differentiate PLC from HPG. From the comparison of the two pulmonary nodule groups with each other, three metabolites with good sensitivity and specificity were selected, whose discriminating ability of PLC from BPN was satisfactory.
CONCLUSION: Through the research of plasma metabolomics, some significant metabolites were detected among PLC, BPN, and HPG, which have the potential to be the promising biomarkers for lung cancer screening and differential diagnosis.

Keywords: Biomarkers; Differential Diagnosis; Lung Cancer; Metabolomics; Screening

DOI: https://doi.org/10.1186/s13019-025-03719-w

Front Immunol. 2025 ;16 1718994

Succinylation heterogeneity in lung adenocarcinoma: from prognostic model to KLK6-driven tumor microenvironment remodeling.

Jichang Liu, Xuehan Zhu, Chenlong Zha, Jiaqi Ding, Chuanpeng Zhang, Yizhe Wang, Tao Yan, Hui Kong, Yong Liu, Jingyu Chen.

Background: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality. Protein succinylation, a key post-translational modification, is implicated in tumor progression. However, its comprehensive landscape and clinical significance in LUAD remain largely unexplored.
Methods: We integrated multi-omics data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. A set of core succinylation-related genes was identified through differential expression and univariable Cox regression analyses. Molecular subtypes based on succinylation were determined by principal component analysis (PCA). A succinylation prognostic model was constructed via least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression. The differences of tumor microenvironment (TME), tumor mutation burden and drug sensitivity in different risk groups were further explored. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics revealed effects of succinylation on TME. High-dimensional weighted gene co-expression networks analysis (hdWGCNA) was used to identify potential succinylation-related therapeutic targets. The function of therapeutic targets was further validated through scRNA-seq, spatial transcriptomics, and in vitro experiments.
Results: We identified 31 core succinylation-related genes and defined three molecular subtypes with distinct prognostic and TME characteristics. A robust 7-gene succinylation-based prognostic signature was developed and validated across 7 independent GEO cohorts, effectively stratifying patients into high- and low-risk groups with significant differences in survival, demonstrating high predictive accuracy, consistency, and clinical utility. The low-risk group exhibited an immunoreactive TME with enhanced immune cell infiltration and superior response to immunotherapy. scRNA-seq and spatial transcriptomics revealed enhanced succinylation in LUAD. Kallikrein-related peptidase 6 (KLK6) was identified as a potential therapeutic target. KLK6 was significantly upregulated in LUAD, correlated with poor prognosis and therapy resistance. KLK6 promoted global succinylation, proliferation, migration, and invasion of LUAD cells in vitro. Mechanistically, KLK6-positive tumor cells might foster an immunosuppressive TME by driving fibroblast-to-myofibroblast differentiation, enhancing extracellular matrix (ECM) deposition, and inhibiting CD8+ T cell infiltration.
Conclusion: Our study delineates the succinylation landscape in LUAD, establishes a novel prognostic model for risk stratification and immunotherapy prediction. Meanwhile, we identified KLK6 as a potential promoter of tumor progression and immunosuppression. Targeting the succinylation pathway, particularly KLK6, may represent a promising therapeutic strategy for LUAD.

Keywords: KLK6; immunotherapy; lung adenocarcinoma; prognosis; succinylation

DOI: https://doi.org/10.3389/fimmu.2025.1718994

Transl Lung Cancer Res. 2025 Nov 30. 14(11): 4838-4848

High GLUT1 protein expression is associated with unfavorable tumor features and poor prognosis in non-small cell lung cancer.

Birgit Hantzsch-Kuhn, Nina Schraps, Martin Reck, Sönke von Weihe, Till Olchers, David Benjamin Ellebrecht, Katharina Moeller, Christoph Fraune, Maximilian Lennartz, Florian Lutz, Martina Kluth, Georgia Makrypidi-Fraune, Ronald Simon, Guido Sauter, Stefan Steurer.

Background: Glucose transporter 1 (GLUT1) is a transmembrane protein responsible for the transportation of glucose across the cell membrane that is often overexpressed in cancer. Due to a key role in cancer glucose metabolism and its membranous localization GLUT1 represents a potential therapeutic target. Our study was designed to elucidate the prevalence of GLUT1 expression and potential associations with tumor phenotype as well as patient outcome in different lung cancer subtypes.
Methods: A tissue microarray containing 858 resected lung cancers was analyzed for GLUT1 expression by immunohistochemistry.
Results: GLUT1 staining was significantly more prevalent and intense in squamous cell carcinoma (SCC, 97.3%) than in pulmonary adenocarcinoma (AC, 62.9%; P<0.001). Of the 225 SCCs, GLUT1 staining was observed in 219 (97.3%) tumors and considered strong in 75.6%, moderate in 15.1%, and weak in 6.7%. In 439 ACs, GLUT1 staining was seen in 276 (62.9%) tumors and considered strong in 14.6%, moderate in 16.4% and weak in 31.9%. High GLUT1 staining was significantly linked to advanced pT stage (P=0.03), nodal metastasis (P<0.001), high grade (P<0.001) and poor overall survival (OS) (P=0.01) in ACs. In SCCs, high GLUT1 staining was unrelated to pT, pN, and histologic grade but significantly linked to OS (P=0.03).
Conclusions: It is concluded that GLUT1 expression is commonly expressed in lung cancer and that a high level of expression is linked to unfavorable tumor features and/or poor prognosis in both AC and SCC.

Keywords: Glucose transporter type 1; biomarkers; immunohistochemistry; lung neoplasms; tumor

DOI: https://doi.org/10.21037/tlcr-2025-422

Transl Lung Cancer Res. 2025 Nov 30. 14(11): 4962-4972

Association of PD-L1 expression with systemic immune parameters in non-small cell lung cancer.

Mary E Gwin, Mitchell S von Itzstein, Jialiang Liu, Farjana J Fattah, Hong Mu-Mosley, Jeffrey A SoRelle, Sheena Bhalla, Jonathan E Dowell, Sawsan Rashdan, Jason Y Park, Donghan M Yang, Yang Xie, David E Gerber.

Background: In non-small cell lung cancer (NSCLC), programmed death-ligand 1 (PD-L1) expression has moderate ability to predict immune checkpoint inhibitor (ICI) benefit. In clinical practice, PD-L1, a cell surface protein, cannot be characterized in currently available blood-based tests such as circulating tumor DNA assays. To understand the biologic effects of PD-L1 more fully and evaluate whether blood-based tests could provide insight into its expression, we determined the association between PD-L1 expression and systemic immune parameters.
Methods: We collected pre- and post-treatment (6-week) peripheral blood samples in patients with NSCLC treated with ICI. Using multiplex panels and cytometry by time of flight (CyTOF), we analyzed specimens for baseline and post-treatment changes in cytokines, autoantibodies, and immune cell populations. We determined the association between case characteristics, immune parameters, and tumor PD-L1 expression (categorized as <1%, 1-49%, and ≥50%) using Chi-square, one-way analysis of variance (ANOVA), and Kruskal-Wallis tests, accounting for multiple comparisons.
Results: A total of 119 patients were included in the analysis, of whom 41 (34%) had PD-L1 expression <1%; 44 (37%), 1-49%; and 34 (29%), ≥50%. PD-L1 expression was not associated with any demographic, tumor, or treatment characteristics. Among 39 cytokines evaluated, baseline levels of macrophage migration inhibitory factor (MIF) were significantly greater in high PD-L1 positive cases. Among 124 autoantibodies included in the analysis, three (anti-aggrecan, -proteoglycan, and -nucleosome) demonstrated significantly greater post-ICI treatment increases in cases with higher PD-L1 expression. In PD-L1 positive cases, baseline abundance of natural killer T (NKT) cells (P=0.001) and activated monocytes (P=0.04) were significantly lower, while post-treatment increases in mature natural killer (NK) cells were significantly greater (P=0.006).
Conclusions: NSCLC PD-L1 expression is associated with few systemic immune parameters, suggesting that effects on anti-tumor immunity may occur predominantly in the tumor microenvironment and that blood-based assays are unlikely to provide meaningful surrogates of this biomarker.

Keywords: Biomarker; cytokines; immune checkpoint inhibitor (ICI); non-small cell lung cancer (NSCLC); programmed death-ligand 1 (PD-L1)

DOI: https://doi.org/10.21037/tlcr-2025-414