A mechanical stimulation-related gene signature predicts prognosis, reflects immune microenvironment remodeling, and identifies COL22A1 as a potential therapeutic target in lung adenocarcinoma

Background Mechanical stimulation is a key biomechanical characteristic of the tumor microenvironment and is involved in tumor progression, immune microenvironment remodeling, and therapy resistance. This study aimed to develop a mechanical stimulation-related gene (MSRG)-based prognostic signature for survival prediction and to explore its association with the tumor immune microenvironment in lung adenocarcinoma (LUAD). Methods We used a multifaceted approach to analyze MSRGs in LUAD. The AUCell algorithm was used to calculate mechanical stimulation scores at the single-cell level, while CellChat and NicheNet analyses were applied to reveal cell–cell communication and ligand-target regulatory patterns under high mechanical stimulation. Mechanical stimulation activity in TCGA-LUAD samples was quantified by ssGSEA, and WGCNA was then performed to identify key gene modules associated with this trait. An integrated machine learning framework was then used to develop a prognostic risk model. Immune infiltration, stromal and immune scores, immune checkpoint-related features, and immune evasion potential were further evaluated. Finally, the selected key gene, COL22A1 , was validated using multiple approaches. Results Analysis of scRNA-seq data demonstrated that mechanical stimulation (MS) scores varied considerably across different cell types. The high-MS subgroup showed enhanced intercellular communication, suggesting active tumor microenvironment remodeling. Furthermore, a prognostic model for LUAD with robust predictive performance was constructed using WGCNA and machine learning algorithms. Notably, the high-risk group showed reduced immune infiltration, higher tumor purity, elevated CD276 expression, and increased TIDE scores, suggesting an immune-cold and immune-evasive microenvironment. In vitro experiments further showed that COL22A1 enhanced the malignant behavior of LUAD cells, indicating its potential as a therapeutic target. Conclusion We established an MSRG-based prognostic signature that not only predicts survival in LUAD but also reflects tumor immune microenvironment remodeling and potential immune escape. Our preliminary findings also suggest that COL22A1 is involved in LUAD progression and may have potential as a therapeutic target.