Targeting mesenchymal monocyte-derived macrophages to enhance the sensitivity of glioblastoma to temozolomide by inhibiting TNF/CELSR2/p65/Kla-HDAC1/EPAS1 axis

May 15, 2025Journal of advanced research

Improving glioblastoma response to temozolomide by targeting specific immune cells and blocking a key inflammatory pathway

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Abstract

A novel subtype of monocyte-derived macrophages, MES-MDM, is identified as a key factor in promoting temozolomide resistance in glioblastoma.

High expression of TREM1 characterizes MES-MDM in hypoxic regions of tumors, contributing to glioblastoma progression.
Hypoxia activates ATF3 transcription, driving the MES-MDM signature.
MES-MDM facilitates the conversion of glioblastoma cells from a less aggressive to a more aggressive subtype.
Histone lysine lactylation, induced by a specific signaling pathway, is linked to this subtype conversion and temozolomide resistance.
Targeting MES-MDM with TREM1 inhibitory peptides has the potential to increase the sensitivity of glioblastoma to temozolomide and enhance anti-PD-1 immunotherapy effectiveness.

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INTRODUCTION: Temozolomide (TMZ) resistance poses a significant challenge to the treatment of aggressive and highly lethal glioblastomas (GBM). Monocyte-derived Macrophages (MDM) within the tumor microenvironment are key factors contributing to TMZ resistance in GBM. Lactate-mediated histone lysine lactylation (Kla) plays a crucial role in the regulation of tumor progression. However, the mechanism through which MDM-induced Kla expression promotes TMZ resistance in GBM remains unclear.

OBJECTIVES: The objective of this study s to identify a subtype of MDM with therapeutic potential target and to elucidate the mechanisms through which this subtype of MDM contributes to tumor malignant progression and TMZ resistance.

METHODS: We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data to evaluate whether mesenchymal (MES) MDM is associated with poor prognosis. By establishing a subtype model of GBM cells for the first time, we validated the mechanism by which MES-MDM promotes subtype conversion of tumor cells. Using patient-derived GBM organoids and an intracranial orthotopic GBM model, we demonstrated that targeting MES-MDM increased GBM sensitivity to TMZ treatment.

RESULTS: We identified a novel MDM subtype, MES-MDM, in the hypoxic niches of the perinecrotic region characterized by high TREM1 expression, which fueled GBM progression. Hypoxia drived MES-MDM signatures by activating ATF3 transcription. MES-MDM facilitated the transition from the NPC to the MES subtype in GBM cells, in which Histone Deacetylase 1 (HDAC1) Kla, induced by the TNF-CELSR2/p65 signaling pathway, promoted this conversion, thereby promoting TMZ resistance. Targeting MES-MDM with TREM1 inhibitory peptides amplified TMZ sensitivity, offering a potential strategy for overcoming resistance to therapy in GBM. Targeting TREM1 enhanced the effectiveness of anti-PD-1 immunotherapy.

CONCLUSION: This study provides a potential therapeutic strategy for patients with MES-subtype GBM by targeting MES-MDM in combination with TMZ or PD-1 antibody treatment.

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Targeting mesenchymal monocyte-derived macrophages to enhance the sensitivity of glioblastoma to temozolomide by inhibiting TNF/CELSR2/p65/Kla-HDAC1/EPAS1 axis

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