Single-cell transcriptomics reveals MAFB-driven macrophage reprogramming and immune divergence in recurrent glioblastoma

BACKGROUND: Glioblastoma (GBM) is the most aggressive and most common type of primary brain tumor, with poor prognosis despite standard therapies. The mechanisms driving recurrence remain poorly understood. Tumor-associated macrophages (TAM) dominate the GBM microenvironment and promote tumor growth, angiogenesis, and immune suppression, yet their activation states and transcriptional programs are not well defined. RESULTS: By integrating large-scale single-cell transcriptomic datasets, we delineate profound immune microenvironmental divergence in recurrent GBM, characterized by the emergence of a distinct CXCL3⁺ tumor-associated macrophage (TAM) population. These CXCL3⁺ TAMs exhibit a robust pro-inflammatory cytokine program, intensified interactions with malignant and immunosuppressive immune cells, and a strong association with poor patient survival. Regulatory network analysis identifies MAFB as the central transcriptional regulator of this TAM state. MAFB is selectively enriched in macrophages, markedly upregulated in recurrent tumors, and strongly correlated with pro-inflammatory gene signatures. Immunohistochemistry and multiplex immunofluorescence further demonstrate an expanded population of MAFB⁺ mesenchymal-like TAMs in recurrent GBM. Depletion of MAFB in patient-derived GBM cells suppresses intracranial tumor growth and prolongs survival in vivo. CONCLUSIONS: Our study highlights profound immune remodeling in primary and recurrent GBM. We further define a MAFB-driven CXCL3⁺ macrophage program that shapes the immune landscape of recurrent GBM and underscore this axis as a promising target for microenvironmental reprogramming.