Genetic drivers shape TREM2-dependent myeloid responses and glioblastoma progression

Glioblastoma (GBM) is characterized by a heterogeneous, myeloid-enriched, and highly immunosuppressive microenvironment. TREM2 regulates microglial and macrophage functions, but its role in GBM remains unclear. We investigated whether genetic drivers determine the effects of TREM2 using de novo and orthotopic transplantable murine models of Nf1-silenced/Ras-driven and PDGFB-driven GBM. To this end, we combined immune profiling, functional assays, secretome analysis, and single-cell RNA sequencing with bone marrow chimeras and conditional Trem2 deletion strategies. Trem2 deficiency prolonged survival and reduced tumor burden in Nf1-silenced/Ras-driven GBM, whereas it increased tumor burden without affecting survival in PDGFB-driven GBM. These different outcomes were accompanied by distinct changes in myeloid composition and soluble mediators. TREM2 was required for bone marrow-derived macrophage migration and microglial process extension towards Ras-derived, but not PDGFB-derived, tumor-conditioned medium. In contrast, both models showed impaired microglial efferocytosis. Single-cell RNA sequencing analysis of Nf1-silenced GBM showed that Trem2 loss shifted myeloid cells from disease-associated, pro-inflammatory states to a more homeostatic state. Bone marrow chimeras supported a tumor-promoting role for TREM2 in microglia, rather than infiltrating myeloid cells in Ras-driven GBM. In addition, conditional deletion of Trem2 before tumor implantation prolonged survival, whereas deletion after tumor establishment did not. These findings identify genetic context and timing of TREM2 activity as determinants of its effects on GBM progression, highlighting driver-dependent myeloid responses as considerations for developing TREM2-directed therapies in glioblastoma.