Comprehensive characterization of lysosome-dependent cell death reveals prognostic significance and immune landscape in colon adenocarcinoma

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Lysosome-dependent cell death (LDCD) is an emerging form of regulated cell death with critical implications in tumor development, immune modulation, and therapy responsiveness. However, the role of LDCD-related genes in colon adenocarcinoma (COAD) remains poorly understood. We comprehensively analyzed LDCD-related gene expression profiles using transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases (GEO). Unsupervised clustering was performed to identify molecular subtypes. A prognostic signature was developed using LASSO and Cox regression analyses. Immune infiltration characteristics and immunotherapy responses were assessed via multiple algorithms. Single-cell RNA sequencing (scRNA-seq) analysis was conducted to explore the cellular distribution of LDCD genes. Functional assays, including colony formation, Transwell migration, and western blotting, were performed to validate the role of key LDCD regulators in COAD cell line. LDCD-related genes were differentially expressed in COAD tissues and stratified patients into two distinct subtypes with significant differences in survival, immune infiltration, and biological pathways. A five-gene prognostic signature demonstrated robust predictive ability for overall survival and was associated with tumor immune microenvironment characteristics. High-risk patients showed distinct immune checkpoint profiles and predicted sensitivity to immune checkpoint blockade therapy. scRNA-seq analysis revealed cell type-specific expression patterns of LDCD genes. In vitro experiments confirmed that modulation of a key LDCD regulator, SLC11A1, affected the proliferation and invasiveness of COAD cells. Moreover, the impact of SLC11A1 on apoptosis and intracellular ROS level confirmed the potential association between SLC11A1 and COAD cell apoptosis. Our study reveals the prognostic value and immunological relevance of LDCD-related genes in COAD. These findings provide new insights into molecular classification and may aid in the development of personalized therapeutic strategies targeting LDCD pathways in colorectal cancer.

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