Harnessing the Membrane Potential to Combat Cancer Progression

Rapid fluctuations in the plasma membrane potential (V_m) provide the basis underlying the action potential waveform in electrically excitable cells; however, a growing body of literature shows that the V_m is also functionally instructive in nonexcitable cells, including cancer cells. Various ion channels play a key role in setting and fine tuning the V_m in cancer and stromal cells within the tumor microenvironment (TME), raising the possibility that the V_m could be targeted therapeutically using ion channel-modulating compounds. Emerging evidence points to the V_m as a viable therapeutic target, given its functional significance in regulating cell cycle progression, migration, invasion, immune infiltration, and pH regulation. Several compounds are now undergoing clinical trials and there is increasing interest in therapeutic manipulation of the V_m via application of pulsed electric fields. The purpose of this article is to update the reader on the significant recent and ongoing progress to elucidate the functional significance of V_m regulation in tumors, to highlight key remaining questions and the prospect of future therapeutic targeting. In particular, we focus on key developments in understanding the functional consequences of V_m alteration on tumor development via the activation of small GTPase (K-Ras and Rac1) signaling, as well as the impact of V_m changes within the heterogeneous TME on immune cell function and cancer progression.