Circulating immune profiling reveals impaired monocyte states and trajectories driving immunosuppression in glioblastoma

Abstract Glioblastoma (GBM) is an aggressive and lethal brain tumor marked by profound local and systemic immune dysfunction. Yet, the diagnostic and therapeutic relevance of peripheral impairments remains undefined. To clinically dissect their underlying mechanisms and pathological implications, we combined mass and flow cytometry with single-cell RNA-sequencing of peripheral blood mononuclear cells from GBM patients and healthy donors. GBM blood profiles were characterized by heterogeneous changes in classical monocytes, encompassing expanded, reduced and unchanged subsets, presenting distinct functional states, including antigen-presenting, interferon and metabolic subsets. Additional adaptations included myeloid-derived suppressor cell (MDSC) expansion and loss of non-classical monocytes. Trajectory analyses positioned MDSCs as an intermediate state, in continuum with the metabolic subset. Single-cell RNA-sequencing further showed antigen-presenting monocyte propensity to differentiate into tumor-associated macrophages. Circulating monocytes shared a “GBM-classical monocytic signature” exhibiting low MHC class II expression, altered cell-cell communication and increased anti-inflammatory mediators, such as IL1R2 and CD163 . Lastly, lymphocyte alterations included decreased proportions of CD4 + T, natural killer (NK) and CD56 + T cells, retaining relatively conserved activation profiles, exemplified by up-regulation of alarmins S100A8/S100A9 . These findings map systemic immune reprogramming in GBM, suggesting new avenues for non-invasive biomarker discovery and therapeutic strategies to restore anti-tumor immunity.