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 Ca2+ 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. 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 Ca2+ 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.