Inactivation of CDK12/13 Pathway Boosts Body’s Immune Response Against Tumors

Immunotherapy uses the body’s immune system to recognize and destroy cancer cells.

One way to do this is through immune checkpoint inhibitors.

Immune checkpoints are a normal part of the immune system, and they help prevent the immune response from destroying healthy cells in the body.

Therapeutic drugs that set up an immune checkpoint blockade inhibit proteins that prevent the immune system from attacking cancer cells.

As a result, T cells can more effectively target and destroy tumors.

However, many patients are resistant to this therapy, which poses a challenge to their treatment.

A study led by researchers from the University of Michigan showed that targeting CDK12 and a related gene, CDK13, strongly activates the stimulator of interferon genes, or STING, signaling pathway, enhancing the effectiveness of immunotherapies.

The work was published in The Journal of Clinical Investigation.

Previously, U-M researchers had identified a new subtype of aggressive prostate cancer and had shown that patients who have lost the CDK12 gene develop metastatic disease.

This finding prompted them to further investigate the role of CDK12.

Using preclinical models, they later found that targeting CDK12/13 results in STING activation.

In this process, CDK12 loss activates other genes that drive cancer.

Both the overexpression of these genes as they try to create proteins and the rapid DNA replication causes a collision, resulting in DNA damage.

In their previous study, the team found that the inactivation of CDK12/13 was associated with higher levels of T cells in advanced prostate cancer.

To understand the connection between the immune system and CDK12/13, the team looked at metastatic prostate cancer samples with either active or inactive CDK12 in the study.

In clinical samples across a broad range of cancer types, they found that inactivation of both CDK12 and CDK13 was associated with higher STING activity and more favorable immunotherapy treatment outcomes.

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The researchers confirmed these findings in preclinical models using a CDK12/13 degrader. Mice treated with this molecule had higher STING activity.

This increased activity was due to the release of DNA fragments inside tumor cells, which is a result of DNA damage triggered by the loss of CDK12/13.

STING activation, in turn, recruited T cells to the tumor, and strongly sensitized them to immune checkpoint blockade, revealing a promising novel strategy to improve current cancer therapies.

“Now the question is whether we will see similar results in clinical trials,” said Arul Chinnaiyan, MD, PhD, SP Hicks Professor of Pathology and member of the Rogel Cancer Center.

“We hope that the CDK12/13 degraders will combine nicely with the immune checkpoint inhibitors in future therapies.

Reference: Bao Y, Chang Y, Tien J, et al. CDK12/13 inactivation triggers STING-mediated anti-tumor immunity in pre-clinical models. J Clin Invest. 2025. doi: 10.1172/JCI193745

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