Clinical and tissue evidence of immune dysregulation in osteosarcoma: altered peripheral neutrophil-related indices and reduced APOE expression.

Background: Osteosarcoma (OS) is a common primary malignant bone tumor in children and adolescents. Increasing evidence suggests that immune dysregulation contributes to OS progression, but its tissue-level and systemic features remain incompletely defined. This study aimed to characterize immune-related alterations in OS and identify key immunoregulatory molecules associated with disease progression. Methods: Public transcriptomic datasets from the Gene Expression Omnibus (GSE14359, GSE19276, GSE21257, GSE28424, and GSE36001) were analyzed using differential expression, functional enrichment, protein-protein interaction analysis, immune-infiltration analysis, and machine-learning algorithms. Public single-cell RNA-seq data from six primary OS samples were additionally analyzed to define the cellular composition of the OS microenvironment and localize APOE expression. Peripheral blood parameters were retrospectively compared between 604 OS patients and 600 hospital-based non-malignant controls with cervical spondylosis. APOE expression was further evaluated by immunohistochemistry in paired tumor and adjacent non-tumor tissues. Results: Five core genes were identified, including APOE, CD74, RPL26L1, WDR12, and CXCL12, among which APOE was significantly downregulated in OS tissues. Immune-infiltration analysis suggested reduced neutrophils and CD8 Conclusions: This study integrates tissue-level, single-cell, and exploratory peripheral hematologic evidence to support immune-related alterations in OS. APOE downregulation and altered peripheral neutrophil-related indices may represent clinically relevant features associated with immune dysregulation in osteosarcoma.