M2 polarization of macrophage protects the lung cancer cells from cold atmospheric plasma via alleviating endoplasmic reticulum stress

Although cold atmospheric plasma (CAP) has been proved to kill various kinds of tumor cells effectively, most previous studies were performed on the in vitro tumor cell model in the absence of tumor microenvironment (TME), resulting in limited insights to its clinical application. Here, we explored the anti-tumor effect of CAP based on a co-culture model of macrophages and lung cancer cells, and it was found that CAP could induce M2 polarization of macrophages and then release IL-10. The released IL-10 activated the STAT1/STAT3 signaling pathway to alleviate CAP-induced endoplasmic reticulum stress in tumor cells, finally resulting in attenuation of programmed death of tumor cells after CAP exposure. In particular, the presence of macrophages caused the reduction of GSDME-dependent pyroptosis, which was proved to play an important role in activation of anti-tumor immunity, induced by CAP. Our findings provide evidences to a better understanding of the anti-tumor effect of CAP and insights to promote the clinical application of CAP tumor therapy.