SMPD1 as a Potential Prognostic Biomarker in Glioma Is Associated With an Immunosuppressive Microenvironment

BACKGROUND: Acid sphingomyelinase (ASM), encoded by SMPD1, regulates sphingolipid metabolism and has been implicated in tumor progression and immune modulation. However, its role in glioma remains poorly defined. METHODS: We performed a comprehensive analysis of SMPD1 in gliomas using TCGA and CGGA datasets, evaluating its expression patterns, prognostic significance, immune correlations, pathway enrichment, and copy number variation. Using qRT-PCR, we validated in vitro the effect of SMPD1 expression on macrophage polarization. Immunofluorescence staining was used to assess the levels of ASM of clinical samples and its correlation with tumor-associated macrophages. The functional role of SMPD1 was further validated in vivo. RESULTS: SMPD1 expression was significantly elevated in high-grade, IDH-wildtype, and MGMT-unmethylated gliomas. High SMPD1 levels were associated with poor prognosis and served as an independent prognostic factor. Tumors with elevated SMPD1 showed increased infiltration of regulatory T cells and M0/M2 macrophages. SMPD1 expression correlated with multiple immune cell markers and immune checkpoint molecules. Cell-based experiments showed that knocking out or inhibiting ASM drives macrophages toward an M1 phenotype while suppressing M2 polarization. Immunofluorescence analysis confirmed upregulation of ASM protein in high-grade, IDH-wildtype gliomas, with a strong positive correlation with CD163 expression in clinical samples. In vivo, inhibition of SMPD1 significantly suppressed glioma growth. CONCLUSION: SMPD1 is a potential biomarker and therapeutic target in gliomas. Its upregulation may contribute to the formation of an immunosuppressive microenvironment and promote tumor progression, highlighting its potential relevance in glioma immunotherapy.