Na⁺/K⁺-ATPase, cardiac glycosides, and tumor immunity

Tumor immunity arises from the coordinated action of innate and adaptive immune systems but is hindered by immune escape within the immunosuppressive tumor microenvironment (TME), for which ion channels and ion pumps have proved to be important. These proteins regulate a wide range of cellular processes to influence cancer progression and immune cell functions, of which ion channels maintain intracellular ion concentrations, cytosolic pH, and cell volume and functions and are essential for cancer development and immune regulation. Ion pumps correlate closely with ion channels and show an important effect on tumor immunity. Of these, H⁺-ATPases, especially vacuolar H⁺-ATPase (V-ATPase), play critical roles in cancer progression, metastasis, and immune evasion, while Na⁺/K⁺-ATPase (NKA) interacts with ion channels and H⁺-ATPase and hence contributes to antitumor immune responses. Thus, several cardiac glycoside inhibitors have been reported to exert potent antitumor and immunomodulatory activities. In the present perspective article, the interconnections among NKA, ion channels, H⁺-ATPases, and immune responses are addressed, with the potential activities of cardiac glycosides on tumor immunity discussed.