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IL-6 underlies microenvironment immunosuppression and resistance to therapy in glioblastoma

Young, Jacob1; Cho, Nam Woo1; Raleigh, David1

Published Mar 02, 2026 on Dryad. https://doi.org/10.5061/dryad.c59zw3rkm

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Abstract

The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor macrophages and myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and therapeutic studies in preclinical models to show that interleukin-6 (IL-6) neutralization reprograms the glioblastoma TIME to sensitize mouse glioblastoma allografts to ICI and ICI plus radiotherapy. We find rare human glioblastomas that achieve clinical responses to ICI have lower pre-treatment IL-6 compared to glioblastomas that do not respond to ICI. We show that diverse immunostimulatory gene therapies suppress IL-6 in mouse glioblastoma allografts, and that IL-6 from multiple cell types the TIME reduces survival in preclinical models and in patients. IL-6 blockade with a neutralizing antibody sensitizes mouse glioblastoma allografts to ICI by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and by decreasing immunosuppressive Tregs. To translate these findings to a therapeutically relevant combination treatment for patients, we show that IL-6 blockade plus ICI sensitizes mouse glioblastoma allografts to ablative radiotherapy.