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 (TAMs) and even tumor cells. However, the function and potential applications of P2X7-mediated immunosuppressive responses in tumor microenvironment remains unclear. Here, we demonstrated that P2X7 was highly expressed in TAMs and that P2X7 deficiency impaired the "M2-like" polarization of TAMs via down-regulation of STAT6 and IRF4 phosphorylation both in vivo and in vitro. 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 immunotherapy (anti-PD-1 antibody) and chemotherapy (cisplatin) were both overcome by co-administration 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 lung cancer patients.