Beyond the gap: moonlighting functions of connexins in cancer.

Connexins are classically defined as the structural subunits of gap junction channels that mediate direct intercellular communication. In cancer, their role has long been interpreted through this canonical role, with loss of gap junction intercellular communication considered permissive for tumor initiation. Although genomic alterations in connexin genes have been identified across diverse malignancies, their mechanistic implications remain poorly defined, and current cancer treatment strategies largely target channel activity alone. However, accumulating evidence demonstrates that connexins also exert important channel-independent, non-canonical functions that reshape oncogenic signaling networks. These "moonlighting" activities, defined as mechanistically distinct functions performed by a single protein, reposition connexins as active regulators of tumor cell behavior rather than passive conduits of small signaling molecules and messengers. Connexin moonlighting functions influence multiple hallmarks of cancer, including proliferation, survival, invasion, and metastatic dissemination, in a context- and stage-dependent manner. These functions help explain the long-standing paradox that connexins can exert both tumor-suppressive and pro-tumorigenic effects. In this Review, we synthesize recent insights into the roles of connexins in cancer, focusing on gap junction-independent functions. We highlight key unresolved mechanistic questions and discuss how an expanded understanding of connexin biology may inform more precise therapeutic strategies.