DNA damage induced by CDK4 and CDK6 blockade triggers anti-tumor immune responses through cGAS-STING pathway

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the cell cycle, and their inhibitors are established anti-cancer drugs.
• Overexpression of CDK4/6 correlates with poor patient survival and reduced T cell infiltration in human cancers.

Purpose of the Study:

• To investigate the STING-dependent immune mechanisms underlying tumor suppression by CDK4/6 blockade.
• To elucidate how CDK4/6 inhibition impacts anti-tumor immunity.

Main Methods:

• Analysis of clinical datasets for CDK4/6 expression, patient survival, and T cell infiltration.
• Tumor growth assessment in Cdk4 or Cdk6 deficient mouse models.
• Investigation of DNA damage and cGAS-STING pathway activation in response to Cdk4/6 deficiency.
• Assessment of anti-tumor effects in Sting knockout models.

Main Results:

• CDK4/6 deficiency in tumor cells significantly reduced tumor growth.
• Cdk4 or Cdk6 deficiency led to increased endogenous DNA damage, activating the cGAS-STING pathway and type I interferon response.
• STING knockout partially or fully reversed the anti-tumor effects of Cdk4/6 deficiency.

Conclusions:

• CDK4/6 blockade promotes anti-tumor immunity through a STING-dependent type I interferon response.
• CDK4/6 inhibitors may serve as a strategy to enhance immunotherapy by boosting innate immune signaling.