Blocking P2X7-Mediated Macrophage Polarization Overcomes Treatment Resistance in Lung Cancer

P2X7, a crucial sensor of extracellular ATP, is widely distributed in different immune cells as a potent stimulant of inflammation and immunity. P2X7 is also highly expressed in immunosuppressive cells such as tumor-associated macrophages (TAM) and even tumor cells. However, the function and potential applications of P2X7-mediated immunosuppressive responses in the tumor microenvironment remain unclear. Here, we demonstrated that P2X7 was highly expressed in TAMs and that P2X7 deficiency impaired the "M2-like" polarization of TAMs via downregulation of STAT6 and IRF4 phosphorylation both <i>in vivo</i> and <i>in vitro</i> P2X7 deficiency restricted the progression of urethane-induced lung carcinogenesis and Lewis lung cancer by decreasing tumor cell proliferation and angiogenesis, promoting T-cell mobilization, and reversing M2-like TAM polarization. Thus, deletion or blockade of P2X7 was therapeutic for lung cancer. Furthermore, resistance to both immunotherapy (anti-PD-1 antibody) and chemotherapy (cisplatin) was overcome by coadministration of the P2X7 inhibitors O-ATP, A-438079 hydrochloride, and A-740003. Therefore, our data revealed a vital role of P2X7 in tumor formation through regulating TAM polarization, suggesting the therapeutic potential of P2X7 blockade in patients with lung cancer.