Connexin hemichannels as therapeutic targets in glioblastoma

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains largely incurable because of diffuse invasion, cellular heterogeneity, therapy resistance, and recurrence. These traits depend not only on tumor-intrinsic programs but also on dynamic interactions between glioma cells and the tumor microenvironment. Connexins are extensively remodeled in GBM and are best known for forming gap junction channels, whose broad inhibition risks disrupting essential homeostatic functions in the healthy brain. By contrast, connexin hemichannels (HCs) are regulated plasma membrane conduits that can open under inflammatory, hypoxic, oxidative, and metabolic stress. Here, we review evidence that connexin HCs may act as conditionally activated amplifiers of tumor–microenvironment signaling in GBM. We discuss connexin expression in normal brain and GBM, with emphasis on Cx43, Cx46, Cx26, and Cx30, and examine how HC opening may influence glutamate and ATP release, macrophage/microglia-associated inflammation, neuronal hyperexcitability, vascular remodeling, metabolic adaptation, and redox signaling. We distinguish direct evidence from GBM models from mechanistic inferences derived from related systems. Emerging studies indicate that HC-targeting interventions can reduce GBM invasiveness, alter extracellular ATP and glutamate accumulation, modulate tumor-associated pathology, and attenuate network hyperexcitability in preclinical models. We conclude that connexin HCs are promising but incompletely validated therapeutic targets at the GBM tumor–microenvironment interface and highlight the need for biomarkers of pathological HC activation in human tumors.