Abstract
BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common type of tumor globally and the leading cause of cancer-related deaths. Although treatment strategies such as immune checkpoint inhibitors and chemotherapy have advanced, the heterogeneity among NSCLC patients results in significant variability in treatment outcomes. Studies have shown that certain patients respond poorly to immune checkpoint inhibitors, indicating that treatment response is closely related to multiple factors. Therefore, it is necessary to develop predictive models to stratify patients based on gene expression and clinical characteristics, aiming for precision therapy. OBJECTIVE: This study aims to construct a stratified prognostic model for NSCLC patients based on lysosome-dependent cell death (LDCD) scoring by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. By analyzing the immune-related characteristics of high-risk and low-risk groups, we further explored the impact of cell death patterns on lung cancer and identified potential therapeutic targets. METHODS: This study obtained single-cell RNA sequencing data and gene expression data of NSCLC patients and normal lung tissues from the GEO and TCGA databases. We used R packages such as Seurat and CellChat for data preprocessing and analysis, and performed dimensionality reduction and visualization through Principal Component Analysis (PCA) and UMAP algorithms. LASSO regression analysis was used to construct the predictive model, followed by cross-validation and ROC curve analysis. The model's effectiveness was validated through survival analysis and immune microenvironment analysis. RESULTS: The study showed a significant increase in the proportion of monocytes in NSCLC tissues, suggesting their important role in cancer progression. Cell communication analysis indicated that macrophages, smooth muscle cells, and myeloid cells exhibit strong intercellular communication during cancer progression. Using the constructed prognostic model based on 12 LDCD-related genes, we found significant differences in overall survival and immune microenvironment between the high-risk and low-risk groups.