Purpose <p>To investigate the expression patterns of the immune factor Lysozyme (LYZ) across pan-cancer, with a focus on elucidating its prognostic value, molecular mechanisms, and association with the immune microenvironment in glioma, aiming to identify novel therapeutic targets for precision oncology.</p> Methods <p>Utilizing The Cancer Genome Atlas (TCGA) pan-cancer datasets, we analyzed differential expression of LYZ between tumor and normal tissues, correlated clinical features, tumor stemness, and prognosis. Univariate/multivariate Cox regression was performed to assess the independent impact of LYZ on glioma prognosis. A nomogram was constructed and validated across multi-center cohorts (including our center, TMA, CGGA datasets). Correlations between LYZ and immune checkpoints/immune cell infiltration were evaluated, with GO/KEGG enrichment analysis to reveal underlying regulatory pathways.</p> Results <p>LYZ was significantly overexpressed in 23 cancer types (including glioma). In glioma, high LYZ expression inversely correlated with stemness but showed complex associations with genomic instability. TCGA data revealed that elevated LYZ was strongly associated with worse overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI), with hazard ratios (HR) of 3.94, 4.02, and 2.31, respectively, and all P values &lt; 0.001.Multivariate models confirmed its independence from WHO grade (HR = 1.471, <i>P</i> = 0.037), validated consistently across multi-center cohorts (<i>P</i> &lt; 0.001). LYZ positively correlated with immune infiltrates (e.g., macrophages) and modulated antigen presentation and innate immune pathways.</p> Conclusion <p>LYZ is aberrantly overexpressed in glioma, serving as an independent prognostic biomarker. It may promote tumorigenesis by reshaping the immune microenvironment, offering potential synergy with immune checkpoint blockade as a therapeutic target.</p>