LAUSR

HighlightsCx43 regulates invasiveness, proliferation, and resistance of malignant glioma.Cx43 provides a permissive niche for the invasion and channel‐mediated TMZ resistance.Targeting Cx43 with C‐terminal peptidomimetics can sensitize glioblastoma to TMZ.Mechanism of action for peptidomimetics may be channel‐dependent or channel‐independent. &NA; Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl‐terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra‐tumor and inter‐tumor heterogeneity make it difficult to clearly define specific populations for Cx43‐targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient‐derived stem cells, could provide opportunities for patient‐specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.