Targeting KDM3B Elicits Anti-tumor Immunity by Alleviating SHP1-mediated STING Suppression in Triple-Negative Breast...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immunotherapy shows promise for cancer, but efficacy is limited in triple-negative breast cancer (TNBC) due to an immunosuppressive tumor microenvironment (TME).
• Identifying mechanisms of immune evasion in TNBC is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of lysine demethylase 3B (KDM3B) in immune evasion within the TNBC TME.
• To evaluate KDM3B inhibition as a therapeutic strategy to enhance anti-tumor immunity and immunotherapy response in TNBC.

Main Methods:

• Correlation analysis of KDM3B expression with cytotoxic T lymphocyte (CTL) infiltration in TNBC.
• Genetic and pharmacologic inhibition of KDM3B in TNBC mouse models.
• Mechanistic studies involving KDM3B, SHP1, STING pathway, and type I interferon (IFN) responses.
• Assessment of KDM3B depletion and KDM3B inhibitor (P3FI-90) effects on tumor progression and response to immune checkpoint blockade (ICB) therapy.

Main Results:

• KDM3B expression negatively correlates with CTL infiltration in TNBC.
• KDM3B inhibition promotes CD8+ T cell recruitment and activation, suppressing tumor growth in TNBC models.
• KDM3B suppresses SHP1, leading to STING inactivation and reduced type I IFN responses.
• KDM3B depletion or inhibition with P3FI-90 suppresses tumor progression and overcomes resistance to ICB therapy.

Conclusions:

• KDM3B is a key mediator of immune evasion in TNBC by modulating the TME and T cell responses.
• Targeting KDM3B enhances anti-tumor immunity and holds potential for improving immunotherapy efficacy in TNBC patients.
• KDM3B inhibition represents a promising therapeutic strategy to overcome immune escape in triple-negative breast cancer.