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.
Hu et al. (Sun,) studied this question.