Gap junctions and hemichannels in cancer: A "Wired versus Broadcast" framework for tumor microenvironment routing of cGAMP-STING signals and therapy response.

Intercellular communication in the tumor microenvironment (TME) dictates cancer progression, immune evasion, and therapy response. Gap junctions (GJs, primarily connexins), connexin hemichannels, and pannexin channels have been widely reviewed, but a unified conceptual model that contrasts protected "Wired" versus vulnerable "Broadcast" routing of cGAMP and ATP in the TME, and links this routing to therapy response, has been lacking. We propose a "Wired vs Broadcast" framework to define the routing of TME danger signals. "Wired" signaling, via connexin 43 (Cx43) gap junction intercellular communication, mediates contact-dependent, protected transfer of the immunotransmitter 2´3´-cGAMP from tumor cells to recipient cells, activating the STING pathway. "Broadcast" signaling, via PANX1 channels and related extracellular release routes, releases ATP and extracellular cGAMP into the TME, where they are intercepted and neutralized by ectoenzymes such as ENPP1 and CD39/CD73. This framework highlights context-dependent, recipient-cell-dependent outcomes of "Wired" signaling: a tumor-to-antigen-presenting cell (APC) "Wired" circuit can drive anti-tumor immunity and support immune checkpoint blockade (ICB) responsiveness, whereas a tumor-to-astrocyte "Wired" circuit can promote brain metastasis and chemoresistance. The relative contributions of "Wired" and "Broadcast" routing, shaped by cellular proximity, scaffolding proteins, transport and uptake mechanisms, and ectoenzyme expression, may influence therapeutic response in a context-dependent manner. This review synthesizes current evidence into an integrative and testable "Wired versus Broadcast" framework and discusses biomarker and combination-therapy hypotheses that can be evaluated in forthcoming spatial-omics and clinical studies.