NR1D1 deficiency in the tumor microenvironment promotes lung tumor development by activating the NLRP3 inflammasome.

Nuclear receptor Rev-erbα (NR1D1) is a major negative regulator of the circadian clock. Numerous studies have investigated the role of circadian clock-related factors in the tumorigenesis of multiple cancer types, but little is known about the role of NR1D1 in cancer development. In this study, we identified the role of NR1D1 in lung tumorigenesis using genetically engineered mouse models of Nr1d1. Although NR1D1 overexpression or knockdown had little effect on the proliferation of NSCLC cells in vitro, NR1D1 deficiency in the tumor microenvironment increased lung cancer development compared with the control in the orthotopic model. NR1D1-deficient mice showed increased NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation, and conditioned medium (CM) from NR1D1-deficient macrophages increased the proliferation and epithelial-mesenchymal transition (EMT) of lung cancer cells. Treatment with MCC950, a specific inhibitor of NLRP3 inflammasome, blocked tumorigenesis in NR1D1-deficient mice in an orthotopic lung cancer model. In addition, MCC950 treatment blocked the increased proliferation and EMT of cancer cells induced by CM from NR1D1-deficient macrophages in vitro. Our results showed that NR1D1 in the tumor microenvironment functions as a tumor suppressor by negatively regulating the NLRP3 inflammasome, suggesting that the NLRP3 inflammasome blockade via NR1D1 activation could be a therapeutic strategy to overcome lung cancer.