Adrenergic Signaling in Immunotherapy of Cancer: Friend or Foe?

Simple Summary Exercise is associated with many aspects of a healthy lifestyle. Among these, exercise leads to the secretion of adrenaline and noradrenaline, which mobilize cells of the immune system, a process which is suggested to possess therapeutic value in cancer therapy, alone or in combination with immunotherapy. Strikingly, administration of beta-blockers-which block the effect of adrenaline/noradrenaline-are also suggested to be useful in cancer therapy alone or in combination with immunotherapy. Herein we discuss the question of whether exercise and the administration of beta-blockers could potentially be useful in cancer therapy. The incidence of cancer is increasing worldwide, which is to a large extent related to the population's increasing lifespan. However, lifestyle changes in the Western world are causative as well. Exercise is intrinsically associated with what one could call a "healthy life", and physical activity is associated with a lower risk of various types of cancer. Mouse models of exercise have shown therapeutic efficacy across numerous cancer models, at least in part due to the secretion of adrenaline, which mobilizes cells of the immune system, i.e., cytotoxic T and natural killer (NK) cells, through signaling of the beta-2 adrenergic receptor (beta 2AR). Clinical trials aiming to investigate the clinical value of exercise are ongoing. Strikingly, however, the use of beta-blockers-antagonists of the very same signaling pathway-also shows signs of clinical potential in cancer therapy. Cancer cells also express beta-adrenergic receptors (beta ARs) and signaling of the receptor is oncogenic. Moreover, there are data to suggest that beta 2AR signaling in T cells renders the cell functionally suppressed. In this paper, we discuss these seemingly opposing mechanisms of cancer therapy-exercise, which leads to increased beta 2AR signaling, and beta-blocker treatment, which antagonizes that same signaling-and suggest potential mechanisms and possibilities for their combination.