Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

The pharmacological modulation of the immunosuppressive tumor microenvironment has emerged as a relevant component for cancer therapy. Several approaches aiming to deplete innate and adaptive suppressive populations, to circumvent the impairment in antigen presentation, and to ultimately increase the frequency of activated tumor-specific T cells are currently being explored. In this review, we address the potentiality of targeting the voltage-gated proton channel, Hv1, as a novel strategy to modulate the tumor microenvironment. The function of Hv1 in immune cells such as macrophages, neutrophils, dendritic cells, and T cells has been associated with the maintenance of NADPH oxidase activity and the generation of reactive oxygen species, which are required for the host defense against pathogens. We discuss evidence suggesting that the Hv1 proton channel could also be important for the function of these cells within the tumor microenvironment. Furthermore, as summarized here, tumor cells express Hv1 as a primary mechanism to extrude the increased amount of protons generated metabolically, thus maintaining physiologic values for the intracellular pH. Therefore, because this channel might be relevant for both tumor cells and immune cells supporting tumor growth, the pharmacological inhibition of Hv1 could be an innovative approach for cancer therapy. With that focus, we analyzed the available compounds that inhibit Hv1, highlighted the need to develop better drugs suitable for patients, and commented on the future perspectives of targeting Hv1 in the context of cancer therapy.