Integrative bioinformatics identifies GRIN2D-associated immune reprogramming and correlates it with drug sensitivity in lung adenocarcinoma

Lung cancer is the leading cause of cancer-related deaths worldwide. It is characterised by complex molecular mechanisms, high rates of treatment resistance, and intricate disease progression mechanisms. Lung adenocarcinoma is the most common histological subtype of lung cancer, and its malignant progression is closely associated with the remodelling of the tumour immune microenvironment. However, the role of the N-methyl-D-aspartate receptor subunit 2D (GRIN2D) in lung adenocarcinoma remains unclear. In this study, integrated data from TCGA, GEO, and single-cell transcriptomic datasets revealed that GRIN2D is significantly overexpressed in lung adenocarcinoma tissues and associated with reduced overall survival in patients, representing an independent prognostic factor. Single-cell analysis showed that GRIN2D is primarily expressed in myeloid cells and fibroblasts. Fibroblast-related signalling pathways involving the CXCL12-CXCR4, GAS6/PROS1-AXL, and FGF signalling axes were significantly enhanced in tumour tissues. Following virtual knockout of GRIN2D, differentially expressed genes were predominantly enriched in processes such as extracellular matrix remodelling, TGF-β signalling, integrin signalling, and focal adhesion, suggesting that GRIN2D may promote tumour microenvironment remodelling by regulating fibroblast function and intercellular communication. Furthermore, GRIN2D expression was associated with immune cell infiltration and sensitivity to various antitumour drugs. In summary, GRIN2D may act as a key hub molecule linking lung adenocarcinoma cell proliferation, matrix remodelling, and immune regulation. This represents a new theoretical basis and highlights a potential target for prognostic stratification and the optimisation of targeted intervention strategies for lung adenocarcinoma.