2. Academic Validation
  3. IL-1β+ tumor-associated macrophages accelerate glioblastoma progression by amplifying the PGE2-EP4 signaling

IL-1β+ tumor-associated macrophages accelerate glioblastoma progression by amplifying the PGE2-EP4 signaling

  • J Neuroinflammation. 2025 Oct 14;22(1):233. doi: 10.1186/s12974-025-03551-y.
Hao Liang # 1,  Qunying Yang # 2,  Biling Zhong 3,  Dan Li 4,  Feima Wu 3,  Jian Zhang 1,  Chongqi Guo 3,  Zhengquan Zhu 5,  Min Feng 6,  Yong Zhang 7,  Hui Peng 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Affiliated Guangdong Second Provincial, General Hospital of Jinan University, Guangzhou, 510317, P.R. China.
  • 2 Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China.
  • 3 Department of Pathology, The Affiliated Guangdong Second Provincial, General Hospital of Jinan University, Guangzhou, 510317, P.R. China.
  • 4 Department of Pharmacy, The Affiliated Guangdong Second Provincial, General Hospital of Jinan University, Guangzhou, 510317, P.R. China.
  • 5 Department of Neurosurgery, The Cancer Hospital Affiliated to Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, 830048, P.R. China.
  • 6 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, P.R. China.
  • 7 Department of Neurosurgery, The Affiliated Guangdong Second Provincial, General Hospital of Jinan University, Guangzhou, 510317, P.R. China. zhangyongsey@163.com.
  • 8 Department of Pathology, The Affiliated Guangdong Second Provincial, General Hospital of Jinan University, Guangzhou, 510317, P.R. China. hpeng392@163.com.
  • # Contributed equally.
PMID: 41088217 DOI: 10.1186/s12974-025-03551-y
Abstract

Glioblastoma (GBM) harbors a highly inflammatory microenvironment driven predominantly by activated innate immune cells, despite being classified as an immunologically cold tumor due to limited T cell infiltration. Tumor-associated macrophages (TAMs) are key contributors to disease progression, in part through their production of interleukin-1β (IL-1β), a pro-inflammatory cytokine with tumor-promoting functions. However, the precise role of IL-1β⁺ TAMs in GBM remains incompletely understood. This study aimed to elucidate the functional contributions of IL-1β⁺ TAMs to GBM malignancy and to explore their therapeutic relevance. Single-cell RNA Sequencing (scRNA-seq) analysis revealed that IL-1β⁺ TAMs were enriched in GBM tissues compared to normal brain tissue, with their elevated infiltration correlating with aggressive tumor phenotypes and poor prognosis. Functionally, IL-1β stimulated GBM cells to secrete inflammatory mediators such as PGE2 and TNFα. These mediators, in turn, upregulated C/EBPβ expression in macrophages, thereby enhancing IL-1β transcription. Mechanistically, tumor-derived PGE2 and TNFα synergistically activated C/EBPβ via EP4 receptor signaling, initiating a self-sustaining IL-1β-PGE2/TNFα-EP4-C/EBPβ-IL-1β feedback loop that amplified pro-inflammatory crosstalk between GBM cells and TAMs. Disruption of PGE2/EP4 signaling effectively suppressed IL-1β+ TAM generation and attenuated tumor growth in preclinical models. Our finding highlights how GBM cells induce macrophages to secrete IL-1β through the synergistic action of PGE2 and TNFα via the EP4 receptor and C/EBPβ activation. This feedback loop between tumor cells and macrophages fosters a pro-inflammatory TME that drives GBM progression. Targeting the PGE2/EP4-C/EBPβ signaling axis may therefore present a promising immunotherapeutic strategy to disrupt tumor-TAM crosstalk and suppress GBM progression.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03551-y.

Keywords

C/EBPβ; Glioblastoma microenvironment; IL-1β+ macrophages; PGE2; TNFα.

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