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

## TL;DR

SMPD1 is a potential biomarker in glioma linked to poor prognosis and an immunosuppressive environment, suggesting a role in tumor progression and immunotherapy.

## Contribution

This study identifies SMPD1 as a novel prognostic biomarker and therapeutic target in glioma associated with immune cell infiltration and tumor progression.

## Key findings

- High SMPD1 levels correlate with poor prognosis and immunosuppressive tumor microenvironment in gliomas.
- ASM inhibition promotes M1 macrophage polarization and suppresses tumor growth in vivo.
- SMPD1 expression is elevated in high-grade, IDH-wildtype, and MGMT-unmethylated gliomas.

## Abstract

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.

SMPD1 expression varies across different glioma subtypes and clinical features and is associated with poor prognosis. High SMPD1 levels are linked to an immunosuppressive tumor microenvironment, characterized by suppressed M1 macrophage polarization and enhanced M2‐like signatures. In vivo, ASM deficiency was associated with reduced glioma growth. Collectively, these results support SMPD1 as a candidate prognostic biomarker and potential therapeutic target in glioma.