Targeting the IL-6/STAT3–Purinergic Axis in Glioblastoma: Mechanistic Insights and Therapeutic Perspectives

Glioblastoma (GBM) is the most aggressive primary brain tumor and remains associated with poor prognosis despite current therapeutic strategies. Chronic inflammation plays a pivotal role in tumor progression, with the interleukin-6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3) pathway acting as a central regulator of proliferation, angiogenesis, immune evasion, metabolic adaptation, and therapeutic resistance. In parallel, purinergic signaling has emerged as a key component of the glioblastoma microenvironment, where extracellular ATP promotes inflammatory responses while its conversion into adenosine by CD39 and CD73 establishes an immunosuppressive niche that favors tumor progression. Although both pathways have been extensively investigated, their mechanistic crosstalk remains insufficiently explored. This review integrates current evidence on the reciprocal interactions between IL-6/STAT3 and purinergic signaling, highlighting their role in sustaining chronic inflammation, immune suppression, and glioblastoma progression. Additionally, we discuss quercetin as a multitarget bioactive compound capable of modulating IL-6/STAT3, NF-κB, PI3K/Akt, oxidative stress, and potentially purinergic-related pathways. Complementary exploratory molecular docking identified potential binding modes of quercetin with IL-6, STAT3, CD39, the A2A receptor, and P2 × 4, providing structural hypotheses for its modulation of this signaling network. Finally, we address current translational challenges and future therapeutic perspectives focused on simultaneous modulation of inflammatory and purinergic signaling. Overall, this review proposes the IL-6/STAT3–purinergic axis as an integrated mechanistic framework underlying glioblastoma biology and highlights multitarget therapeutic strategies as promising approaches for future translational research. The IL-6/STAT3–purinergic axis constitutes a self-amplifying signaling network that integrates chronic inflammation, immune suppression, and metabolic adaptation, thereby promoting glioblastoma progression and therapeutic resistance. Quercetin is highlighted as a multitarget compound capable of modulating several components of this interconnected molecular network