Inositol metabolism shapes tumor aggressiveness and immune evasion in lower-grade glioma: an integrative analysis of bulk, single-cell, and spatial transcriptomics.

Background: Emerging clinical evidence has linked inositol levels to clinical features in lower-grade glioma (LGG). However, the architecture and functional significance of inositol metabolism remain poorly defined.

Materials and methods: We developed a transcriptome-based inositol-related gene score (INScore) to quantify inositol metabolic status in LGG, leveraging patient subtypes identified through non-negative matrix factorization (NMF) of inositol-related gene expression profiles. A cohort of 1,659 LGG patients from six independent datasets was analyzed to evaluate the prognostic value of INScore. A comprehensive multi-omics framework-encompassing bulk transcriptomics, single-cell RNA sequencing, spatial transcriptomics, genomic profiling, and clinical data-was employed to elucidate the biological implications of INScore. The hub gene was identified via LASSO regression and validated through functional assays and clinical sample analysis.

Results: The INScore model demonstrated significant prognostic power across all cohorts, with higher INScore correlating with poorer survival outcomes. Bulk transcriptomic and genomic analyses revealed that elevated INScore correlated with oncogenic signaling activation, increased genomic instability, and a macrophage-driven immunosuppressive tumor microenvironment. Single-cell and spatial transcriptomic profiling further delineated two high-INScore glioma subtypes: Glioma_C5, characterized by reduced apoptosis, impaired differentiation, and increased copy number variation burden; and Glioma_C8, marked by extensive macrophage interactions promoting immune suppression. IMPA2 was identified as the hub gene within the inositol metabolic network, with its knockdown significantly impairing LGG cell proliferation and invasion, and its overexpression enhancing malignant phenotypes. Immunohistochemical analysis confirmed that IMPA2 expression was positively associated with both M2 macrophage polarization and poor clinical outcomes.

Conclusion: Inositol metabolism status serves as a potent prognostic biomarker in LGG, intricately linked to tumor aggressiveness and immune evasion, highlighting its potential as a therapeutic target.