Are connexin hemichannels playing any role in cancer?

Abstract

Connexin (Cx) hemichannels have emerged as key regulators of both physiological and pathological processes. They exhibit a dual role in cellular function: while low-to-moderate activity supports cell-to-cell communication, excessive hemichannel opening can be detrimental, leading to cell death. In the context of cancer, the contribution of Cx hemichannels remains poorly defined. However, evidence from various models suggests that their activity may critically influence cancer progression. For example, Cx hemichannels mediate the release of signaling molecules such as ATP, which, upon conversion to adenosine, contributes to immunosuppression within the tumor microenvironment (TME). Notably, the activity of Cx hemichannels is modulated by several intracellular and extracellular factors—many of which are disrupted in tumors—suggesting that their regulatory dynamics in cancer may differ substantially from those under homeostatic conditions. This review aims to explore the potential roles of Cx hemichannels in shaping the TME, promoting immune evasion, and facilitating tumor progression. Given their putative relevance, future studies should focus on elucidating how cancer-associated alterations in regulatory mechanisms affect Cx hemichannel activity and whether such activity contributes to tumor aggressiveness. A clearer understanding of these processes may uncover novel therapeutic opportunities targeting Cx hemichannel regulation in oncology.