Immunotherapy uses a person’s own immune system to fight cancer.

Immune checkpoint inhibitors are one class of immunotherapy that block specific proteins from slowing the immune response. As a result, immune cells become more active and can more effectively kill cancer cells.

However, most patients either respond poorly to checkpoint inhibitors or eventually become resistant to the treatment.

In a study published in Nature, University of Michigan researchers have identified that the balance between two proteins—STAT3 and STAT5—is important for making tumors vulnerable to immune checkpoint therapy, and targeting STAT3 degradation is a potential novel cancer immunotherapy strategy.

“Resistance to cancer immunotherapy is a huge issue for cancer patients,” said Weiping Zou, M.D., Ph.D., professor of surgery and pathology and a member of Rogel Cancer Center.

“That’s why it’s important to understand the underlying mechanisms and figure out how to deal with this problem.”

As Zou describes, the immune system is like a military unit.

T cells function as soldiers and are responsible for killing tumor cells.

There are also generals, such as dendritic cells, that give out instructions on where and how the T cells are needed.

Dendritic cells patrol tissues, capture proteins that look abnormal and present these to T cells, thereby activating them.

Using RNA sequencing databases of cancer patients, the researchers found that STAT3 and STAT5 work together to control the quantity of dendritic cells.

Although researchers have known that STAT3 is a cancer target for many years, these results uncovered a previously unknown mechanism of immune checkpoint resistance."

- Shaomeng Wang, Ph.D.

Through transcriptional signaling, each protein activates different types of genes that affect how dendritic cells function.

Patients who were responsive to checkpoint inhibitors had higher STAT5 signaling and lower STAT3 signaling.

Using mouse models, the researchers showed that STAT3 counteracts the effects of STAT5, preventing dendritic cells from maturing and activating T cells.

The results were consistent across different tumors, including those in the skin, ovary, breast, lung and colon.

“Although researchers have known that STAT3 is a cancer target for many years, these results uncovered a previously unknown mechanism of immune checkpoint resistance,” said Shaomeng Wang, Ph.D., professor of internal medicine and pharmacology and a member of Rogel Cancer Center. 

“Unfortunately, STAT3 is also hard to target and has been considered undruggable.”

In this study, the team turned to a system that already exists in our body.

“Our bodies contain a protein degradation system, which clears out damaged proteins,” Wang said. 

“Our approach was to recruit that machinery to degrade STAT3.”

The team developed and used two types of molecules, SD-36 and SD-2301, to target STAT3 for protein degradation. In both cell lines and mouse models, STAT3 degradation in dendritic cells boosted immunity and increased STAT5 signaling.

Both molecules were also effective in treating large, advanced tumors and those that were resistant to immune checkpoint inhibitors.

“Our next step is to conduct clinical trials of our most promising STAT3 degraders,” Zou said.

“Since STAT3 is often activated in many cancer types, we are hopeful that these molecules will help a large population of patients.”

Additional authors: Jiajia Zhou, Kole Tison, Haibin Zhou, Longchuan Bai, Ranjan Kumar Acharyya, Donna McEachern, Hoda Metwally, Yu Wang, Michael Pitter, Jae Eun Choi, Linda Vatan, Peng Liao, Jiali Yu, Heng Lin, Long Jiang, Shuang Wei, Xue Gao, Sara Grove, Abhijit Parolia, Marcin Cieslik, Ilona Kryczek, Michael D. Green, Jian-Xin Lin, Arul M. Chinnaiyan and Warren J. Leonard

Funding/disclosures: The study was supported by the Breast Cancer Research Foundation, the National Cancer Institute through the National Institutes of Health (CA217648, CA123088, CA099985, CA193136, CA152470, and CA244509) and the NIH/NCI through the University of Michigan Rogel Cancer Center Grant (CA46592). J-X Lin and Leonard are supported by the Division of Intramural Research, the National Heart, Lung, and Blood Institute and NIH.

Tech transfer(s)/Conflict(s) of interest: Zou serves as a scientific advisor or consultant for Cstone, Hanchor Bio, and NextCure and was a consultant for Oncopia. S. Wang was a co-founder and a paid consultant for Oncopia Therapeutics and owned equity in Oncopia, which was acquired by Roivant Sciences and Proteovant Therapeutics; was a paid consultant for Proteovant Therapeutics and Roivant Sciences and owned stock in Roivant Sciences; S. Wang was the principal investigator for a research contract between Oncopia/Proteovant and the University of Michigan and is a co-founder, paid consultant, and member of the board of directors of Ascentage Pharma Group International and owns stock in Ascentage. Chinnaiyan was a co-founder and a paid consultant for Oncopia and owned equity in Oncopia and was a paid consultant for Proteovant Therapeutics.

The University of Michigan owned stock in Oncopia and Ascentage. The University of Michigan has filed multiple patents on STAT3 degraders, which have been licensed by Oncopia/Proteovant (now SK Life Science Labs). S. Wang, Zhou, Lin, Bai, Acharyya, McEachern and Metwally are inventors on SD-36 and/or SD-2301 and have received royalty payments from the University of Michigan.

Paper cited: “STAT5 and STAT3 Balance Shapes Dendritic Cell Function and Tumor Immunity,” Nature. DOI: 10.1038/s41586-025-09000-3.

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