Antitumor and immunomodulatory activities of diphyllin and its derivatives

Immune surveillance plays a key role in controlling tumor formation and development, and immune cell-based therapies, such as chimeric antigen receptor (CAR)-T cells and CAR-natural killer (NK) cells, have become important for the treatment of cancer. The proton pump (PP), vacuolar H⁺-ATPase (V-ATPase), acidifies intracellular organelles, pumps protons across the cell plasma membranes, and regulates the activity of various signaling pathways, and thus has been regarded as a potential target for cancer treatment. In addition, V-ATPase plays an important role in cytotoxic T lymphocytes, extracellular vesicle (EV) endocytosis, innate immune responses (IIR), and phagocytosis and hence has the potential to function as a target for the enhancement of immunotherapy. As potent V-ATPase inhibitors, the arylnaphthalene lignans, diphyllin and its derivatives, have exhibited potent antitumor and immunomodulatory activities. The structurally related aryltetralin lignan, podophyllotoxin, has served as a lead compound for both etoposide and teniposide, which have been developed as effective anticancer agents. In the present review, the role of V-ATPase in cancer immunotherapy and the structure-activity relationships (SARs) of diphyllin and its cytotoxic and V-ATPase inhibitory activities and the mechanisms of action are discussed. Also, the promise of diphyllin and its derivatives in the development of new adjuvants for cancer immunotherapies has been proposed.