KCa3.1 channels regulate the tumor infiltration of functionally competent NK cells in head and neck cancer

CD8⁺ T cells and natural killer (NK) cells are the primary defenses against tumor cells. The tumor microenvironment impairs their antitumor capabilities, including the ability to infiltrate the tumor. Our laboratory has shown that tumors suppress T cells by inhibiting KCa3.1 K⁺ channel activity that controls cytokine release, cytotoxicity, and chemotaxis. However, little is known about the role of K⁺ channels in the anti-tumor activity of NK cells. Here, we investigated KCa3.1 channels' role in human NK cell function in head and neck squamous cell carcinoma (HNSCC). Selective blockade of KCa3.1 using TRAM-34 inhibited chemotaxis of NK cells from both healthy donors and patients with HNSCC, while KCa3.1pharmacological activation increased chemotaxis and cytotoxicity. SKA-31, a selective KCa3.1 activator, enhanced antitumor immune responses in a humanized HNSCC mouse model generated by implanting Cal27 cells and healthy donor peripheral blood mononuclear cells into immunodeficient mice. SKA-31 treatment resulted in a 7-fold increase in total NK cells and a 23-fold increase in functionally active (granzyme B-positive) NK cells in these tumors. These data highlight the critical role of KCa3.1 channels in antitumor immunity and open the possibility of targeting KCa3.1 to develop new immunotherapies for HNSCC.