Connexin-Pannexin duality in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, characterized by extensive heterogeneity and diffuse invasion. Increasing evidence highlights the role of channel-forming proteins in glioma biology. Connexins (Cxs) and Pannexins (Panxs) are two structurally related yet functionally distinct protein families that mediate cellular communication. While both regulate overlapping processes such as ion homeostasis and ATP release, only Cxs are capable of readily forming intercellular gap junctions. Cx43 is the most extensively studied connexin in GBM and seems to display paradoxical roles, acting as a tumour suppressor by reducing proliferation while promoting invasion. In contrast, Panx1 predominantly supports tumour progression, while Panx2 exerts tumour-suppressive effects. This review synthesizes how Cxs and Panxs exert context-dependent and sometimes opposing effects across stages of GBM, including proliferation and invasion, and examines how divergent experimental models may contribute to apparent contradictions. Discrepancies among studies often arise from differences in model systems, which may not recapitulate the complexity of human GBM. Given the profound heterogeneity of this tumour, future research should prioritize patient-derived and three-dimensional models that more accurately represent the human disease context. Such approaches will be essential to clarify the context-dependent functions of Cxs and Panxs and their potential as therapeutic targets in GBM.