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.

Ovarian cancer (OC) remains a leading cause of gynecologic cancer mortality worldwide, highlighting the need for novel immunomodulatory therapies. Immunoge