Anal Bioanal Chem. 2026 Jul 27. doi: 10.1007/s00216-026-06702-z. Online ahead of print.

ABSTRACT

Protein glycosylation is a major post-translational modification that regulates tumor initiation and progression; however, its dynamic modeling during multistep evolution of lung adenocarcinoma (LUAD) remains poorly understood, particularly in clinically archived tissues. Here, we established an integrated multi-omics workflow combining global proteomes, N-glycans, and site-specific intact N-glycopeptides to comprehensively characterize glycosylation in formalin-fixed paraffin-embedded (FFPE) specimens spanning four pathological stages of LUAD progression: inflammatory nodules (IN), atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and invasive adenocarcinoma (IAC). Using optimized protein extraction, hydrophilic interaction liquid chromatography (HILIC)-based glycopeptide enrichment, and high-resolution LC-MS/MS, we achieved large-scale identification of proteins, N-glycans, and intact glycopeptides from archival clinical samples. Integrated analyses revealed progressive remodeling of site-specific N-glycosylation during malignant transformation, characterized by increased glycan branching, fucosylation, and sialylation during the transition from premalignant lesions to invasive cancer. Sialylated glycans reached their highest abundance in the premalignant AAH stage, whereas highly branched and fucosylated complex N-glycans predominated in invasive adenocarcinoma, indicating stage-dependent glycan remodeling throughout disease progression. Functional enrichment analyses linked these glycosylation alterations to extracellular matrix organization, neutrophil degranulation, and immune-associated pathways, while representative glycoproteins, including CEACAM6 and FGB, exhibited coordinated changes in protein abundance and site-specific glycoform micro-heterogeneity across pathological stages. Collectively, this study demonstrates the feasibility of deep glycoproteomic profiling using archived FFPE tissues and provides a comprehensive molecular atlas of glycosylation remodeling during LUAD progression. These findings establish a valuable resource for elucidating disease mechanisms and identifying stage-specific glycosylation biomarkers and potential glycan-targeted therapeutic candidates for early lung adenocarcinoma.

PMID:42509285 | DOI:10.1007/s00216-026-06702-z

Crit Rev Oncol Hematol. 2026 Sep;225:105483. doi: 10.1016/j.critrevonc.2026.105483. Epub 2026 Jul 10.

ABSTRACT

Low-dose CT (LDCT) lung cancer screening significantly reduces mortality but has dramatically increased the detection of pulmonary nodules. Most of these nodules are benign, leading to a high false-positive rate that triggers unnecessary invasive procedures and patient anxiety, underscoring the need for more precise noninvasive diagnostic tools. Critically, single-modality liquid biopsy biomarkers, including circulating tumor cells, cell-free DNA mutations, or individual microRNAs, have demonstrated insufficient sensitivity or specificity for independent clinical deployment when used in isolation. This necessitates a paradigm shift toward multimodal molecular integration, wherein complementary biomarker classes are combined to overcome the inherent limitations of any single analyte. Traditional clinical prediction models (Mayo, VA, Brock, Herder) assist in estimating malignancy risk, yet their accuracy remains modest. Emerging approaches harness radiomics and artificial intelligence (AI) to extract high-dimensional imaging features from chest CT scans, improving risk stratification beyond human assessment alone. In parallel, minimally invasive liquid biopsy biomarkers offer complementary avenues to detect occult malignancy signals. Additionally, bronchial airway gene expression classifiers leverage the "field-of-injury" effect in normal respiratory epithelium to help identify lung cancer even when the nodule itself cannot be directly sampled via biopsy. Integrating these radiologic and molecular data streams into a multi-omics framework has the potential to enhance diagnostic precision for indeterminate pulmonary nodules, enabling more confident discrimination between benign and malignant lesions. However, most of these emerging tools have not yet been validated in large prospective trials and face technological barriers as well as challenges in real-world implementation. This review focuses primarily on LDCT screening detected pulmonary nodules, while incorporating evidence from incidentally detected and other indeterminate nodule cohorts when relevant to broader CT based management. By synthesizing advances in radiomics, AI, liquid biopsy, airway classifiers, and multi-omics integration, we highlight the need for prospective validation and multidisciplinary collaboration to translate these approaches into clinically useful pathways that improve early lung cancer detection, reduce unnecessary interventions, and enhance patient outcomes.

PMID:42431477 | DOI:10.1016/j.critrevonc.2026.105483

Front Immunol. 2026 Jun 18;17:1855906. doi: 10.3389/fimmu.2026.1855906. eCollection 2026.

ABSTRACT

Pulmonary gas exchange and host defense depend on the dynamic coordination of resident and recruited macrophage populations. Historically, macrophage functions have often been interpreted through the classic M1/M2 dichotomy; however, this binary framework does not capture the heterogeneity and context-dependent plasticity of macrophage states within the lung microenvironment. Advances in single-cell RNA sequencing and spatial multi-omics have substantially refined our understanding of this complex macrophage network. Here, we synthesize evidence from human studies and experimental models to summarize macrophage functional states in homeostasis and across chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, acute lung injury/acute respiratory distress syndrome, and lung cancer. We highlight how macrophage transcriptional programs are shaped by ontogeny, tissue niche, and epigenetic-metabolic regulation, and how these programs are linked to disease-specific remodeling of the pulmonary microenvironment. Across diverse respiratory diseases, persistent tissue injury and microenvironmental stress remodel resident macrophage programs and are frequently accompanied by the expansion and context-dependent differentiation of recruited monocyte-derived macrophages. These macrophage states are associated with inflammatory amplification, epithelial and endothelial barrier dysfunction, extracellular matrix remodeling, and tumor immune evasion. Ligand-receptor and spatial analyses further identify candidate communication axes linking macrophages with stromal, epithelial, endothelial, and immune cells, some of which appear partially conserved across disease contexts. Emerging macrophage-targeted strategies are increasingly being explored beyond broad depletion, with growing interest in context-specific reprogramming and niche modulation, including antibody-based, nanocarrier-mediated, and engineered-cell approaches. Decoding the spatiotemporal trajectories and cell-cell communication networks of specific macrophage subsets, while considering tissue context, species differences, and levels of experimental support, may help clarify mechanisms of tissue remodeling, therapeutic resistance, and macrophage-targeted intervention in complex pulmonary diseases.

PMID:42396453 | PMC:PMC13322945 | DOI:10.3389/fimmu.2026.1855906

Chin Med J Pulm Crit Care Med. 2026 Jun 6;4(2):99-116. doi: 10.1016/j.pccm.2026.05.005. eCollection 2026 Jun.

ABSTRACT

Lung diseases-including lung cancer, chronic obstructive pulmonary disease (COPD), asthma, interstitial lung diseases (ILDs), and rare conditions like cystic fibrosis-remain major drivers of global morbidity and mortality. Timely diagnosis and individualized treatment are frequently challenged by heterogeneous clinical phenotypes and the complexity of multimodal data. This review provides a critical synthesis of the transformative role of artificial intelligence (AI) in respiratory care, tracing the paradigm shift from classical machine learning to emerging large language models (LLMs) and multimodal foundation models. We evaluate the performance of AI across the patient care continuum: beginning with radiologist-level nodule detection and automated diagnostics, advancing into AI-powered clinical decision support systems (CDSS) and surgical/radiotherapeutic interventions, and culminating in prognostic modeling and "digital twin" simulations for longitudinal patient management. Furthermore, we explore the translational frontier of precision medicine, examining how AI leverages multi-omics and liquid biopsies to drive novel biomarker discovery and accelerate drug repurposing. Finally, we address persistent sociotechnical barriers-including data sovereignty, legal liability, and the critical need for prospective clinical validation-proposing a translational roadmap for the safe integration of generalist medical AI into clinical workflows.

PMID:42396189 | PMC:PMC13323542 | DOI:10.1016/j.pccm.2026.05.005

Curr Med Imaging. 2026 Jun 22. doi: 10.2174/0115734056460566260609044755. Online ahead of print.

ABSTRACT

Lung cancer is the most common and fatal malignant tumour. Early detection and treatment are likely to reduce mortality, but most pulmonary nodules identified during routine health checks are harmless. Consequently, a clear distinction between benign and malignant nodules is vital to improve early detection and reduce unnecessary interventions. Radiomics, a new omics technology, can be used to extract high-dimensional quantitative features from medical images, providing a profound understanding of tumour pathophysiology. Radiomics has attracted the attention of medical researchers since its formal definition by the Dutch researcher Lambin et al. in 2012. The number of research papers on radiomics has grown tremendously over the past few years. At present, it is used to predict pulmonary nodule malignancy, for noninvasive risk stratification, for integration with genomics to identify genetic mutations associated with lung cancer, and for evaluation of therapeutic responses. With this review, we summarise the literature on radiomics of pulmonary nodules, discuss how it could be used in nodule management, and address the current challenges and future directions for improving precision oncology.

PMID:42333843 | DOI:10.2174/0115734056460566260609044755

J Thorac Dis. 2026 May 31;18(5):537. doi: 10.21037/jtd-2026-1-0315. Epub 2026 Apr 30.

ABSTRACT

BACKGROUND AND OBJECTIVE: Lung cancer remains one of the leading causes of cancer-related death worldwide. Although low-dose computed tomography (LDCT) has improved early detection, false-positive results, overdiagnosis, and interobserver variability continue to limit screening efficiency and downstream management of pulmonary nodules. This narrative review summarizes recent progress in artificial intelligence (AI)-assisted screening, radiomics-based nodule characterization, and multi-omics integration for the precision diagnosis of lung cancer.

METHODS: A narrative review with thematic analysis was conducted using representative literature on AI-assisted lung cancer screening, quantitative imaging analysis of pulmonary nodules, radiogenomic and multi-omics integration, and clinical translation challenges. Studies were synthesized to highlight technical advances, diagnostic performance, strengths, limitations, and barriers to implementation.

KEY CONTENT AND FINDINGS: AI improves nodule detection, second-reader support, workflow efficiency, and malignancy-risk estimation in LDCT screening. Radiomics converts CT images into quantitative features that can improve discrimination between benign and malignant nodules, especially when combined with clinical variables or deep-learning models. Beyond imaging alone, radiogenomic and other multi-omics approaches link imaging phenotypes with molecular alterations, treatment response, and prognosis, thereby supporting more individualized management. However, current evidence remains limited by dataset heterogeneity, retrospective design, limited interpretability, and insufficient multicenter prospective validation.

CONCLUSIONS: AI-based imaging and multi-omics integration offer a promising pathway toward earlier detection and more precise diagnosis of lung cancer. Broader clinical adoption will depend on standardized data acquisition, robust external validation, interpretable models, and careful governance of privacy, ethics, and workflow integration.

PMID:42306713 | PMC:PMC13266817 | DOI:10.21037/jtd-2026-1-0315

J Transl Med. 2026 Jun 8;24(1):776. doi: 10.1186/s12967-026-08382-w.

ABSTRACT

BACKGROUND: The molecular distinction between benign and malignant pulmonary nodules remains a significant diagnostic challenge. While genomic drivers are well studied, multiomic integration of the epigenetic-transcriptional landscape and its translation into noninvasive tools are lacking.

METHODS: We performed a multiomic characterization (genomic, epigenomic, and transcriptomic) of 158 pulmonary nodules. Unsupervised factor analysis integrated these layers to identify core regulatory axes. A 9-gene cell-free DNA (cfDNA) methylation classifier was developed and validated in blood and tissue cohorts.

RESULTS: Genomic profiling revealed EGFR mutations (exclusive to malignant nodules) and MYC amplification as fundamental initiators of malignancy. Multiomic factor analysis (Factor 1) revealed profound genetic‒epigenetic synergy, in which these alterations dictate a permissive methylome, leading to aberrant epigenetic programming of chromatin accessibility, as well as epigenetic-transcriptional effects: hypomethylation at the promoters of cell cycle genes that augments their expression, and hypermethylation at immune related pathways gene loci that silences their transcription. This effect orchestrates formation of proproliferative (E2F target/G2M checkpoint) and "immune-cold" malignant phenotype, characterized by elevated Treg/CD8+ ratios and fibroblast recruitment. Notably, we observed a gradual accumulation of methylation aberrations along the premalignant-to-invasive continuum (adenocarcinoma in situ [AIS]→minimally invasive adenocarcinoma [MIA]→adenocarcinoma [ADC]), identifying progressive epigenetic dysregulation as a hallmark of tumor aggressiveness. Global methylome remodeling drives ADC progression through hypermethylation-mediated silencing of tumor suppressors (RASA3 and PPARG) and hypomethylation-activated oncogenic axes, specifically the GDF15 axis, which independently predict poor survival in patients with lung ADC in the TCGA cohort. We translated these tissue-derived insights into a 9-gene cfDNA methylation classifier, which achieved exceptional diagnostic accuracy across independent cohorts (training AUC = 1.00; test AUC = 0.93; tissue AUC = 0.96). Rooted in the biological "ground truth" of tissue dysregulation, this classifier functions specifically as a functional readout of the core cell cycle and proliferative pathways, offering a robust, noninvasive tool for the biology-informed risk assessment of pulmonary nodules.

CONCLUSIONS: This study delineates an epigenetic-transcriptional regulatory network that drives nodule malignancy. Our findings provide a robust theoretical foundation and a high-performance liquid biopsy tool for the precise, noninvasive diagnosis of pulmonary nodules.

PMID:42260586 | PMC:PMC13274191 | DOI:10.1186/s12967-026-08382-w