Multi-omics analysis reveals the prognostic value and immunomodulatory role of CTSW in breast cancer.

backgroundThe inherent complexity and biological heterogeneity of breast cancer pose substantial challenges to the development of effective personalized therapies. The exploration of novel biomarkers, particularly those linked to the tumor immune microenvironment (TME), presents promising opportunities. This study employed a multi-omics framework to investigate the potential regulatory role of cysteine proteases in breast cancer, aiming to identify and characterize novel prognostic markers and strategic therapeutic targets.

methodsWe employed a comprehensive in silico analysis utilizing transcriptomic, methylomic, quantitative trait locus, and genome-wide association studies data. Differentially expressed genes (DEGs) were identified using established statistical tools. Their prognostic significance was assessed through Cox regression and Kaplan-Meier survival analyses. Mendelian randomization (MR) was used to infer potential causal relationships between gene expression and breast cancer risk. Functional enrichment analysis and immune infiltration assessment were performed to elucidate the biological context of DEGs. Single-cell RNA sequencing data provided high-resolution insights into the TME, and protein-protein interaction networks identified key biological pathways.

findingsCTSW emerged as a gene of critical prognostic significance. High CTSW expression was strongly correlated with improved patient survival across breast cancer subtypes. Causal inference via MR provided strong genetic evidence supporting a protective role for CTSW against breast cancer risk. Functional enrichment analysis implicated CTSW in key immune-related pathways, including T-cell activation. Crucially, single-cell analysis revealed that CTSW expression was not only enriched in activated CD8 + T cells but its intrinsic per-cell expression was highest within the triple negative breast cancer (TNBC) subtype, suggesting CTSW reflects the functional quality, not merely the quantity, of T-cell infiltration. This heightened expression in activated CD8 + T cells was strongly associated with a better prognosis. Finally, DNA methylation analysis suggested that epigenetic silencing contributes to CTSW's downregulation in breast cancer. INTERPRETATIONS: This study underscores the pivotal role of CTSW in breast cancer immunology, positioning it as a key indicator of a potent anti-tumor immune response within the TME. Collectively, our findings establish a robust, data-driven hypothesis that CTSW's high expression, particularly in TNBC, reflects a favorable, functionally active immune state. This comprehensive in silico investigation substantiates CTSW's potential as a prognostic biomarker and provides a strong rationale for its future experimental validation as a therapeutic target.