Transl Cancer Res. 2026 Apr 30;15(4):314. doi: 10.21037/tcr-2025-aw-2503. Epub 2026 Mar 20.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common lung cancer subtypes worldwide, and its aggressive subtype invasive adenocarcinoma (IAC) has low survival rates. The precise identification of IAC is vital for the clinical diagnosis and treatment. The purpose of this study is to identify novel biomarkers for LUAD using single-cell and bulk RNA sequencing, so as to provide theoretical basis and practical support for the diagnosis, treatment and prognosis evaluation of lung invasive adenocarcinoma.

METHODS: We employed a combination of transcriptomic analysis and single-cell analysis to investigate the molecular characteristics and immune microenvironment of four subtypes of LUAD, including atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and IAC, with the aim of screening for biomarkers to differentiate pre-invasive lesions from invasive lesions.

RESULTS: Transcriptomic and single-cell analyses revealed that IAC subtypes demonstrated the most substantial molecular differences, particularly in immune cell infiltration and immune-related gene expression. Three genes-CD27, TIGIT, and TNFRSF18-that were significantly upregulated in IAC, predominantly expressed in immune cells and closely linked to immune regulatory pathways. We further analyzed T cell subpopulations in the IAC subtype and explored the expression of transcription factors (TFs) corresponding to these three genes, revealing their critical roles in immune cell function. Additionally, communication between T cells and other cells showed significantly enhanced signaling pathways, particularly those related to immune co-stimulatory molecules and inflammation pathways. Immunohistochemical validation of clinical samples showed that these three genes have high diagnostic value in IAC subtypes. These findings establish a crucial biological foundation for diagnosis, classification, and immunotherapy of LUAD, which contributes to the development of individualized treatment strategies.

CONCLUSIONS: This study identifies a three-gene signature (CD27, TIGIT, and TNFRSF18) that not only distinguishes invasive from pre-invasive LUAD with high precision by capturing the immune checkpoint disequilibrium characteristic of IAC, but also provides a clinically actionable biomarker panel for preoperative diagnosis and personalized immunotherapy strategies.

PMID:42180871 | PMC:PMC13190665 | DOI:10.21037/tcr-2025-aw-2503