Structural Dynamics of Microtubules in Glioma: Impact on Macrophage M2 Polarization and Tumor Cell Heterogeneity

Background: Glioma is the most common malignant brain tumor, characterized by high heterogeneity and poor prognosis. Microtubule dynamics regulate tumor progression and immune escape; however, the prognostic significance of microtubule-associated genes in glioma and their immunological significance still lack systematic investigation. Methods: We integrated transcriptomic and clinical data from TCGA and CGGA cohorts to identify microtubule-associated genes with prognostic significance. A risk score (RS) model was established using Cox regression and validated in independent cohorts. Spatial transcriptomics and single-cell RNA sequencing were applied to characterize the expression patterns of candidate genes across glioma microregions and immune cell populations. Functional enrichment analysis, immune infiltration assessment, and drug sensitivity profiling were performed to explore the biological mechanisms and clinical implications of the RS model. Results: We identified 18 microtubule-associated genes that are significantly associated with glioma prognosis and constructed a four-gene RS model, which robustly predicts overall survival. Tumors with high-RS exhibited increased infiltration of M2 macrophages, enhanced immunosuppressive signaling, and reduced sensitivity to alkylating agents. Spatial and single-cell analyses confirmed that core RS genes are enriched at the tumor-immune interface and shaped macrophage polarization dynamics. Conclusion: Our findings highlight microtubule-associated genes as key regulators of the glioma immune microenvironment. The RS model serves as a clinically applicable biomarker for prognostication and therapeutic stratification, with potential implications for optimizing immunotherapy and chemotherapy strategies in glioma patients.