Abstract
The presence of self-renewing glioblastoma (GBM) stem cells (GSCs) and infiltrating pro-tumor macrophages constitutes two key hallmarks of GBM. Here, we identified the neuropeptide adrenomedullin (ADM) as a key factor regulating GSC-macrophage symbiosis. Epidermal growth factor receptor (EGFR) overexpression upregulates ADM in GSCs to enhance their self-renewal, glycolysis, and tumor growth by activating the signal transducer and activator of transcription 3 (STAT3) pathway. GSC-secreted ADM promotes macrophage infiltration and pro-tumor reprogramming through activation of ADM receptor (ADMR), thereby engaging both STAT3 and STAT6 pathways. In GBM mouse and patient-derived xenograft (PDX) models, inhibition of the ADM-ADMR axis, STAT3, or STAT6 suppresses tumor progression, GSC self-renewal, and pro-tumor macrophage abundance, with dual inhibition of STAT3 and STAT6 leading to durable complete tumor regression in a subset of tumor-bearing mice. In human GBM tumors and plasmas, ADM correlates positively with GSC stemness, pro-tumor macrophage abundance, and poor prognosis. These findings highlight ADM-triggered GSC-macrophage symbiosis as a promising therapeutic target for GBM.