Development of a method to enhance cancer immunity by microcurrent stimulation targeting the circadian clock system of macrophages

<p>It is pointed out that the circadian clock has been involved in the resistance to the treatment of cancer immunotherapies. One of the factors is that the circadian clock is closely related to the function of macrophages(Mφ), the starting point of tumor immunity, but no effective countermeasures are currently available. On the other hand, we have established a method to regulate the biological clock by noninvasive microcurrent stimulation (MCS)¹. In this study, we analyzed the effects of MCS on Mφ.</p><p>Firstly, we observed cellular changes induced by MCS on Mφ using RAW264.7, suggesting that MCS does not affect Mφ differentiation into M1 or the immune checkpoint, but acts on actin polymerization and increases motility. To evaluate the effect of MCS on the phagocytosis of Mφ, we examined the effect of MCS using fluorescently labeled beads and found that MCS increased bead phagocytosis of RAW264.7. </p><p>Secondly, we investigated the detailed mechanism by which MCS increases phagocytosis of Mφ. Using NGS analysis as a starting point, we found that MCS alters the circadian clock system, which decreases the expression rhythm of MCS-related kinase (MRK) and that the decreased expression of MRK leads to an increase in phagocytosis, revealing a series of mechanisms by which the decreased expression of MRK causes the increased phagocytosis.</p><p>Finally, the results of MCS on tumor-bearing mouse revealed that MCS exerts its anti-tumor effects by increasing Mφ infiltration into tumors and increasing the tumor phagocytosis of Mφ. The results of this study are expected to lead to the application of MCS as a safe and effective cancer therapy.</p>