Trehalose-driven TFEB Activation Reprograms Immunosuppressive Macrophages in Glioblastoma

Glioblastoma is the most aggressive primary intracranial tumor in adults. It is characterized by a profoundly immunosuppressive tumor microenvironment orchestrated by glioblastoma-associated macrophages. Yet, the molecular signal pathway programming glioblastoma-associated macrophages toward immunosuppressive phenotype remains elusive. Here, we identify transcription factor EB (TFEB) as a critical regulator of macrophage-driven immune suppression in glioblastoma. In human glioblastoma samples, TFEB is upregulated and correlates with macrophage and CD4⁺ T-cell infiltration. However, higher TFEB levels unexpectedly are associated with improved patient survival, while myeloid-specific TFEB ablation accelerates tumor progression with high glioblastoma-associated macrophage infiltration and impairs T-cell priming. Mechanistically, TFEB loss engages p38 MAPK/ERK axis, enhancing autophagic flux and reinforcing immunosuppressive polarization. In contrast, pharmacologic activation of TFEB with trehalose remodels the TME toward an immuno-stimulatory state and markedly suppresses tumor growth. Collectively, our findings position TFEB as a critical regulator of glioblastoma-associated macrophage polarization and provide a deep insight into TFEB-independent modulation as a promising strategy to overcome immunosuppression in GBM.