# Mediation Mendelian randomization analysis of immune cell phenotypes and glioma risk: unveiling the regulation of cerebrospinal fluid metabolites

## TL;DR

This study uses genetic analysis to show how immune cells and cerebrospinal fluid metabolites influence glioma risk, identifying potential new treatment strategies.

## Contribution

The study introduces a mediation Mendelian randomization approach to uncover causal pathways between immune cell phenotypes, metabolites, and glioma risk.

## Key findings

- Nine risk and ten protective immune cell phenotypes were identified for glioma.
- Metabolites like 7-hoca and glycerophosphoinositol partially mediate the relationship between immune cells and glioma.
- Immune modulation and metabolic intervention are suggested as potential therapeutic strategies for glioma.

## Abstract

Gliomas, particularly glioblastoma multiforme (GBM), are the most common primary central nervous system tumors in adults and are notoriously difficult to treat due to their high heterogeneity and invasiveness. Despite advances in molecular diagnostics and personalized therapies, prognosis remains poor. The immune system plays a critical role in glioma progression. This study employed mediation Mendelian randomization analysis to explore the relationships between immune cell phenotypes, cerebrospinal fluid metabolites, and glioma, aiming to uncover potential mechanisms of tumor progression and immune evasion.

In this study, we employed several analytical methods including IVW, MR Egger, Simple mode, Weighted median, and Weighted mode, with IVW results being considered the primary basis. We assessed heterogeneity and pleiotropy, and used leave-one-out analysis to determine sensitivity, ensuring the stability and reliability of the results. The potential mediating effects of cerebrospinal fluid metabolites were investigated to explore the underlying mechanisms linking immune cell function and glioma. The GWAS data for immune cells, cerebrospinal fluid metabolites, and glioma used in this study were sourced from public databases.

We identified nine risk immune cell phenotypes for glioma (such as CD19 on IgD( +) CD24(-)), and ten protective immune cell phenotypes (such as CD11c on monocytes). Mediation analysis revealed that levels of 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-hoca) (MP = − 14.6%) and Palmitoyl dihydrosphingomyelin (d18:0/16:0) (MP = 7.9%) partially mediated the relationship between CD3 on CD39( +) resting Treg cells and glioma. Additionally, 7-hoca levels (MP = − 12.3%) and Phenyllactate (pla) levels (MP = 4.12%) partially mediated the association between FSC-A on NKT cells and glioma. Furthermore, Glycerophosphoinositol levels (MP = − 12.1%) and Orotate levels (MP = − 11.4%) partially mediated the relationship between Granulocyte adenylyl cyclase (Granulocyte AC) and glioma.

This study identified that specific immune cell phenotypes directly influence glioma risk and indirectly modulate this risk through cerebrospinal fluid metabolites. CD19 on IgD( +) CD24(−) B cells were identified as risk factors, while CD11c on monocytes were protective. Metabolites like 7-hoca and glycerophosphoinositol play key mediating roles. These findings enhance our understanding of glioma pathophysiology and suggest that immune modulation and metabolic intervention may be promising therapeutic strategies.

The online version contains supplementary material available at 10.1007/s12672-025-02499-y.