Targeting WRN Helicase in Microsatellite Instable Colorectal Cancer Induces Antitumor Immunity through...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Microsatellite instability (MSI) colorectal cancer (CRC) is often treated with immune checkpoint inhibitors (ICIs).
• A significant portion of MSI CRC patients do not respond to ICIs.
• The DNA helicase WRN is a synthetic lethal target in MSI cancer cells, with inhibitors in clinical trials.

Purpose of the Study:

• To investigate the impact of WRN inhibition on MSI CRC.
• To explore the mechanism by which WRN inhibition affects the tumor immune microenvironment.
• To evaluate the potential of combining WRN inhibitors with anti-PD-1 therapy.

Main Methods:

• Utilized MSI CRC cell lines and preclinical models.
• Investigated cell death mechanisms induced by WRN inhibition.
• Assessed the role of extrachromosomal circular DNA (eccDNA) and LIG3 in WRN inhibition effects.
• Evaluated the combination therapy in syngeneic mouse tumors and patient-derived tumor organoids.

Main Results:

• WRN inhibition selectively triggered cell death in MSI CRC cells, releasing eccDNA.
• Released eccDNA directly stimulated immune cell activation and cytokine production.
• LIG3 deletion abolished the antitumor and immunogenic effects of WRN inhibition.
• WRN inhibition potentiated anti-PD-1 therapy efficacy in MSI CRC models.

Conclusions:

• WRN inhibition induces an antitumor immune response in MSI CRC through eccDNA release.
• LIG3 is crucial for the immunogenic effects of WRN inhibition.
• Combining WRN inhibitors with ICIs is a promising therapeutic strategy for MSI CRC.