STAT3 signaling as an adaptive hub in glioblastoma: Network rewiring, non-coding RNA circuits, and therapeutic vulnerabilities

Glioblastoma is characterized by profound molecular heterogeneity, therapeutic resistance, and an immunosuppressive microenvironment, rendering current treatment strategies largely ineffective. Signal transducer and activator of transcription 3 (STAT3) has long been implicated in glioblastoma progression; however, its persistent activation and limited clinical tractability have remained incompletely understood. Accumulating evidence indicates that STAT3 functions not as a linear downstream effector but as an adaptive signaling hub that integrates diverse oncogenic inputs, microenvironmental cues, and therapy-induced stress responses. In this review, we synthesize recent advances that redefine STAT3 as a central coordinator of glioblastoma plasticity. We discuss canonical and non-canonical mechanisms driving STAT3 activation, including cytokine signaling, receptor rewiring, circRNA-encoded proteins, and tumor microenvironment–derived signals. We further highlight how STAT3 executes its oncogenic functions through transcriptional and epigenetic programs that sustain chromatin accessibility, glioma stemness, and adaptive gene expression. A major focus is placed on multilayered non-coding RNA circuits—encompassing microRNAs, circular RNAs, and ceRNA feedback loops—that fine-tune STAT3 signaling and reinforce malignant phenotypes. Importantly, emerging evidence reveals that STAT3-driven programs are spatially organized within glioblastoma, shaping immune-suppressive niches and contributing to intratumoral heterogeneity and immunotherapy resistance. Finally, we discuss therapeutic vulnerabilities within the STAT3 network, emphasizing the limitations of single-agent inhibition and the promise of network-oriented strategies, including rational combination therapies, ncRNA-based interventions, and exosome-mediated delivery approaches. By framing STAT3 as a network-level adaptive hub, this review provides a unified conceptual framework that may inform precision targeting strategies and improve therapeutic outcomes for patients with glioblastoma. • STAT3 functions as an adaptive signaling hub rather than a linear pathway effector in glioblastoma. • Non-coding RNA circuits and chromatin programs confer plasticity and therapeutic resistance to STAT3 signaling. • Targeting STAT3-centered networks reveals new opportunities for combination and microenvironment-directed therapies.