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

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Potentiating antitumor immunity is a key strategy for cancer treatment, including breast cancer.
• Targeting DNA damage response pathways offers a novel approach to enhance anti-tumor immunity.
• The nuclear receptor NR1D1 (REV-ERBα) has been implicated in inhibiting DNA repair in breast cancer cells.

Purpose of the Study:

• To investigate the role of NR1D1 in regulating antitumor CD8+ T-cell responses.
• To elucidate the molecular mechanisms by which NR1D1 influences the tumor immune microenvironment.
• To evaluate the therapeutic potential of NR1D1 modulation in breast cancer models.

Main Methods:

• Utilized MMTV-PyMT transgenic mice with Nr1d1 deletion for tumor growth and metastasis studies.
• Performed orthotopic allograft experiments to assess the cell-specific role of NR1D1.
• Conducted comprehensive transcriptome analyses to identify associated biological pathways.
• Investigated the cGAS-STING signaling pathway activation and its downstream effects.

Main Results:

• Deletion of Nr1d1 accelerated tumor growth and lung metastasis in MMTV-PyMT mice.
• Loss of NR1D1 in tumor cells, not stromal cells, significantly promoted tumor progression.
• NR1D1 deficiency suppressed type I IFN signaling, CD8+ T cell, and NK cell infiltration.
• NR1D1 activation by SR9009 enhanced type I IFN-mediated immunity, reducing tumor progression and metastasis.

Conclusions:

• NR1D1 plays a critical role in enhancing antitumor CD8+ T-cell responses by promoting cGAS-STING pathway activation.
• NR1D1 suppresses breast cancer progression and metastasis through immune modulation.
• NR1D1 represents a promising therapeutic target for developing novel immunotherapies for breast cancer.