Breaking adaptive oncogenic resistance in glioblastoma via targeting the EGFR-STAT3 axis

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains refractory to current targeted therapies. Among the oncogenic pathways implicated in GBM pathogenesis, epidermal growth factor receptor (EGFR) signaling and the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway have emerged as central drivers of tumor growth, immune evasion, and therapeutic resistance. Despite frequent EGFR amplification and mutation, clinical trials targeting EGFR have yielded disappointing outcomes, underscoring the existence of adaptive resistance mechanisms. Accumulating evidence indicated that persistent STAT3 activation represents a critical compensatory node that sustains oncogenic transcriptional programs even when EGFR signaling is pharmacologically inhibited. Here, we propose that the EGFR-STAT3 axis functions not as a linear signaling cascade, but as an adaptive resistance hub that integrates growth factor signaling, inflammatory cytokines, hypoxia, tumor-associated macrophages, and therapeutic stress. This signaling rewiring promotes glioma stemness, metabolic reprogramming, immune suppression, and resistance to chemotherapy and radiotherapy. This review systematically dissects the molecular mechanisms underlying EGFR-STAT3 crosstalk, highlights non-canonical and microenvironment-driven STAT3 activation, explains past therapeutic failures, and evaluates new therapeutic strategies targeting this axis to overcome therapeutic oncogenic adaptive resistance in glioblastoma.