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

Overview

Abstract

Background: Glioblastoma (GBM) is an aggressive and lethal brain tumor marked by profound local and systemic immune dysfunction. Despite evidence of peripheral immune impairment, the clinical relevance of these alterations for diagnostic or therapeutic purposes remains poorly defined.

Methods: We performed multimodal single-cell profiling of peripheral blood mononuclear cells from a single-center cohort of treatment-naïve GBM patients and healthy donors, integrating mass and flow cytometry with single-cell RNA-sequencing. Unsupervised clustering, pseudo-temporal trajectory analyses and cell–cell communication inference were applied to map immune states and their interactions.

Results: GBM blood profiles were characterized by heterogeneous changes in classical monocytes, encompassing expanded, reduced and unchanged subsets with distinct functional states, including antigen-presenting, interferon and metabolic programs. Additional myeloid adaptations included myeloid-derived suppressor cell (MDSC) expansion and loss of non-classical monocytes. Trajectory analyses identified a differentiation continuum, evolving from antigen-presenting to metabolic monocyte subsets, and positioning MDSCs as an intermediate state. Antigen‑presenting monocytes displayed tumor‑migratory, precursor‑like profiles that corresponded to tumor‑associated macrophages in public GBM datasets. Across subsets, circulating monocytes shared a “GBM-classical monocytic signature” characterized by low MHC class II expression, altered cell–cell communication and upregulation of anti-inflammatory mediators, including IL1R2 and CD163. Notably, complementary myeloid expression signatures were identified across patients, indicating distinct systemic immune phenotypes. In parallel, 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.

Conclusions: These findings delineate systemic immune reprogramming in primary GBM, characterized by coordinated myeloid and lymphocyte alterations. The identification of circulating monocyte states with transcriptional continuity to the tumour microenvironment, alongside distinct patient-level systemic myeloid signatures, provides a framework for exploring peripheral blood as a source of immune biomarkers in GBM.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12974-026-03964-3.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• data.mendeley.com/preview/gth6pct574, at Mendeley Data; found in “Data availability”
• doi:10.17632/gth6pct574.1, at the source; found in “Data availability”
• figshare:33511982, at figshare; found in DataCite

Data availability

The single-cell mass cytometry data has been deposited at Mendeley Data: Cerella, Claudia; Cosma, Antonio; Michelucci, Alessandro (2025), “Circulating immune profiling reveals impaired monocyte phenotypes and trajectories driving immunosuppression in glioblastoma”, Mendeley Data, V1, doi: 10.17632/gth6pct574.1 (https://doi.org/10.17632/gth6pct574.1) (https://data.mendeley.com/preview/gth6pct574?a=5ef7cf0e-9eab-4840-9985-5a61efe975e3). Flow cytometry data are available from the corresponding author on reasonable request. The single-cell RNA-sequencing data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001008497. Further information about EGA can be found on (https://ega-archive.org) "The European Genome-phenome Archive in 2021" (https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkab1059/6430505).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 7 keywords, 7 MeSH terms, 2 funders, 72 references.

Cite

This paper

Scafidi, A., Kaoma, T., Cerella, C., Campus, E., Grzyb, K., Nosirov, B., Lind-Holm Mogensen, F., Klein, E., Da Costa, R., Skupin, A., Hertel, F., Berchem, G., Mittelbronn, M., Cosma, A., Melin, B., Niclou, S. P., Nazarov, P. V., Golebiewska, A., Poli, A., & Michelucci, A. (2026). Circulating immune profiling reveals impaired monocyte states and trajectories driving immunosuppression in glioblastoma. Journal of neuroinflammation, 23(1), 306. https://doi.org/10.1186/s12974-026-03964-3

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