CD11c ⁺ microglia promote dysfunctional T cell activation in diffuse midline glioma

Paediatric diffuse midline glioma (DMG) remains refractory to immunotherapy despite T-cell infiltration, indicating that local mechanisms actively suppress anti-tumour immunity. Using complementary genetic and orthotopic mouse models, we performed lineage-resolved profiling of the DMG immune microenvironment, resolving myeloid ontogeny and microglial states by distinguishing resident microglia from infiltrating bone marrow-derived macrophages. We identified microglia as the predominant tumour-associated myeloid population and discovered selective expansion of CD11c⁺ microglia exhibiting enriched antigen-presentation and immune-regulatory transcriptional programs. Tumour-infiltrating CD4⁺ and CD8⁺ T cells exhibited chronic activation and exhaustion, while ligand–receptor analysis predicted inhibitory microglia–T cell communication. Pharmacological CSF1R inhibition depleted CD11c⁺ microglia, attenuated antigen-presentation and immune-regulatory programs, and shifted tumour-infiltrating T cells toward a less exhausted phenotype. Together, these findings identify a previously unrecognised CD11c⁺ microglia–T-cell axis that establishes immune dysfunction in DMG and provide a rationale for combining myeloid- and T cell-targeted immunotherapies.