Clinical Potential of Nerve Input to Tumors: A Bioelectricity Perspective.

We support the notion that the neural connections of the tumor microenvironment (TME) and the associated 'bioelectricity' play significant role in the pathophysiology of cancer. In several cancers, the nerve input promotes the cancer process. While straightforward surgical denervation of tumors, therefore, could improve prognosis, resulting side effects of such a procedure would be unpredictable and irreversible. On the other hand, tumor innervation can be manipulated effectively for therapeutic purposes by alternative novel approaches broadly termed "electroceuticals." In this perspective, we evaluate the clinical potential of targeting the TME first through manipulation of the nerve input itself and second by application of electric fields directly to the tumor. The former encompasses several different biophysical and biochemical approaches. These include implantable devices, nanoparticles, and electroactive polymers, as well as optogenetics and chemogenetics. As regard bioelectrical manipulation of the tumor itself, the "tumor-treating field" technique, applied to gliomas commonly in combination with chemotherapy, is evaluated. Also, as electroceuticals, drugs acting on ion channels and neurotransmitter receptors are highlighted for completeness. It is concluded, first, that electroceuticals comprise a broad range of biomedical tools. Second, such electroceuticals present significant clinical potential for exploiting the neural component of the TME as a strategy against cancer. Finally, the inherent bioelectric characteristics of tumors themselves are also amenable to complementary approaches. Collectively, these represent an evolving, dynamic field and further progress and applications can be expected to follow both conceptually and technically.