Multi-omics profiling identifies ACP2 as a lysosome-associated biomarker linked to immune dynamics and clinical outcomes in glioma.

Glioma progression is shaped by molecular heterogeneity, therapy resistance, and an immunosuppressive tumor microenvironment. Lysosomal remodeling has emerged as a hallmark of glioma adaptation; however, the regulation of individual lysosomal enzymes to malignant progression remains poorly understood. Lysosomal acid phosphatase 2 (ACP2) has been implicated in developmental and metabolic disorders, but its role in glioma has not been systematically investigated. In this study, we conducted an integrative multi-omics analysis to define the transcriptional, clinical, functional, and cellular correlates of ACP2 in glioma. Bulk RNA-seq datasets from TCGA and CGGA were used to analyze gene expressions, survival modeling, and machine-learning-based prognostic classification to evaluate the predictive contribution of ACP2 across glioma grades. Immune infiltration was quantified using TIMER2.0. Functional pathways were assessed using MetaCore, KEGG, GO, and Hallmark GSEA. Single-cell RNA-seq and single-nucleus RNA-seq analyses provided cell-type and subtype-specific validation. Protein-protein interactions were examined using STRING and GeneMANIA. Further pharmacogenomic associations were examined using GDSC/CTRP, and molecular docking was performed to simulate the drug ability of ACP2. Findings of this study indicated that ACP2 was significantly overexpressed in glioma relative to normal tissues and demonstrated the strongest prognostic impact among ACP family members. Elevated ACP2 expression correlated with reduced overall survival across multiple independent cohorts and was associated with increased infiltration of macrophages, neutrophils, and dendritic cells. Enrichment analyses revealed consistent activation of PI3K/AKT, KRAS, E2F and extracellular matrix remodeling pathways. MetaCore identified APP processing and cytoskeletal remodeling as top ACP2-associated modules. Single-cell and single-nucleus analyses localized ACP2 expression mainly to malignant glioma and myeloid populations, with higher expression in recurrent and advanced malignant states. This multi-omics framework identified ACP2 as a lysosomal regulator of glioma aggressiveness and immune remodeling. ACP2 functions as a robust biomarker of malignancy and may represent a candidate target for therapeutic exploration in glioma.