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

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.

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.

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.

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.