Integrative Single-Cell and Radiomics Analyses Identify N-Acetylneuraminate Synthase (NANS)-High Signature Associated with Adverse Prognosis and Immune Remodeling in Glioblastoma

Glioblastoma (GBM) is characterized by marked heterogeneity and an immunosuppressive microenvironment. N-acetylneuraminate synthase (NANS) contributes to tumor-associated metabolic regulation, but its relationship with GBM and its immune profile remains unclear. This study aimed to characterize the prognostic and immune relevance of NANS and develop an MRI radiomics model for noninvasive prediction of NANS-high GBM. Prognostic genes were screened across TCGA-GBM and two CGGA cohorts. Bulk transcriptomic and single-cell RNA sequencing analyses were used to evaluate NANS expression, patient survival association, and cellular localization. NANS-high bone marrow-derived macrophages (BMDMs) were characterized using functional enrichment and CellChat analyses. A NANS-high BMDM signature was validated in TCGA-GBM for immune infiltration and ligand–receptor axis activity. Drug sensitivity and CMap analyses were performed. MRI radiomics features were extracted from preprocessed T1 contrast-enhanced and FLAIR images, and an elastic net logistic regression model was constructed to predict NANS-high BMDM signature status. NANS was identified as a prognostic macrophage-associated biomarker in GBM and was enriched in BMDMs. NANS-high BMDMs showed enrichment of mTORC1 signaling, oxidative phosphorylation, unfolded protein response, glycolysis, hypoxia, and protein secretion programs. Cell–cell communication analysis revealed enhanced outgoing signaling toward malignant tumor states and T-cell subsets, with LGALS9-centered interactions representing the dominant differential communication program. In TCGA-GBM, the NANS-high BMDM signature correlated with increased macrophage infiltration, broad immune infiltration, and elevated LGALS9 and PLAU axis scores. Drug sensitivity analyses suggested potential vulnerabilities involving PI3K/mTOR and MAPK/ERK pathways. The radiomics model selected six MRI features and distinguished NANS-high from NANS-low tumors with an AUC of 0.795 (95% CI, 0.652–0.939); bootstrap validation showed a mean AUC of 0.793 (95% CI, 0.637–0.922). NANS-high BMDMs define a prognostically adverse and potentially targetable macrophage-associated phenotype in GBM. MRI radiomics may noninvasively predict this NANS-high BMDM state, supporting imaging-based risk stratification and therapeutic selection.