Data from NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling

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<div>Abstract<p>Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8<sup>+</sup> T-cell responses. First, deletion of <i>Nr1d1</i> in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of <i>Nr1d1</i> in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell–mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8<sup>+</sup> T cells and natural killer cells in tumors were suppressed in <i>Nr1d1</i><sup>−/−</sup>;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage–induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN–mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8<sup>+</sup> T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer.</p>Significance:<p>NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer.</p></div>