CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cyclin-dependent kinase 12 (CDK12) inactivation is linked to an immunogenic prostate cancer subtype with genomic instability.
• This subtype exhibits increased T cell infiltration within tumors.

Purpose of the Study:

• To investigate the role of CDK12 and its paralog CDK13 in cancer immunity.
• To explore the therapeutic potential of targeting CDK12/13 for cancer treatment.

Main Methods:

• Genetic and pharmacologic inactivation of CDK12 and CDK13 in various cancer models.
• Analysis of clinical cohorts correlating CDK12/13 expression with patient survival and response to immune checkpoint blockade (ICB).
• Investigating the mechanism of STING pathway activation upon CDK12/13 depletion, including cytosolic nucleic acid release.

Main Results:

• CDK12/13 inactivation robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types.
• Reduced CDK12/13 expression correlates with improved survival and better response to ICB.
• CDK12/13 depletion or degradation triggers STING activation, delays tumor growth, and synergizes with anti-PD-1 therapy.
• Combination therapy enhances STING activity, CD8+ T cell infiltration, and activation in tumors, dependent on STING and CD8+ T cells.

Conclusions:

• STING activation is a key mechanism driving T cell infiltration and immune-hot microenvironments in CDK12-mutant cancers.
• Dual CDK12/13 inhibitors and degraders can activate anti-tumor immunity.
• Targeting CDK12/13 holds promise for potentiating responses to cancer immunotherapies.