How the Potassium Channel Response of T Lymphocytes to the Tumor Microenvironment Shapes Antitumor Immunity

SIMPLE SUMMARY: Ion channels are proteins that control the movement of ions across the membranes of cells, thus regulating their physiological functions. In T lymphocytes, ion channels control the Ca(2+) influx that, in turn, promotes proliferation and effector functions. In the context of cancer, T cells have the role of fighting tumor cells. However, the tumor microenvironment negatively regulates T cell antitumor capabilities. Therefore, it is of utmost importance to understand the relationship between the tumor microenvironment and the ion channel apparatus of T cells to overcome the tumors’ immunosuppressive capabilities. ABSTRACT: Competent antitumor immune cells are fundamental for tumor surveillance and combating active cancers. Once established, tumors generate a tumor microenvironment (TME) consisting of complex cellular and metabolic elements that serve to suppress the function of antitumor immune cells. T lymphocytes are key cellular elements of the TME. In this review, we explore the role of ion channels, particularly K(+) channels, in mediating the suppressive effects of the TME on T cells. First, we will review the complex network of ion channels that mediate Ca(2+) influx and control effector functions in T cells. Then, we will discuss how multiple features of the TME influence the antitumor capabilities of T cells via ion channels. We will focus on hypoxia, adenosine, and ionic imbalances in the TME, as well as overexpression of programmed cell death ligand 1 by cancer cells that either suppress K(+) channels in T cells and/or benefit from regulating these channels’ activity, ultimately shaping the immune response. Finally, we will review some of the cancer treatment implications related to ion channels. A better understanding of the effects of the TME on ion channels in T lymphocytes could promote the development of more effective immunotherapies, especially for resistant solid malignancies.