STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity

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, Warren J. Leonard, Shaomeng Wang () and Weiping Zou ()
Additional contact information
Jiajia Zhou: University of Michigan Medical School
Kole Tison: University of Michigan Medical School
Haibin Zhou: University of Michigan Medical School
Longchuan Bai: University of Michigan Medical School
Ranjan Kumar Acharyya: University of Michigan Medical School
Donna McEachern: University of Michigan Medical School
Hoda Metwally: University of Michigan Medical School
Yu Wang: University of Michigan Medical School
Michael Pitter: University of Michigan Medical School
Jae Eun Choi: University of Michigan Medical School
Linda Vatan: University of Michigan Medical School
Peng Liao: University of Michigan Medical School
Jiali Yu: University of Michigan Medical School
Heng Lin: University of Michigan Medical School
Long Jiang: University of Michigan Rogel Cancer Center
Shuang Wei: University of Michigan Medical School
Xue Gao: University of Michigan Medical School
Sara Grove: University of Michigan Medical School
Abhijit Parolia: University of Michigan Medical School
Marcin Cieslik: University of Michigan Medical School
Ilona Kryczek: University of Michigan Medical School
Michael D. Green: University of Michigan Rogel Cancer Center
Jian-Xin Lin: National Institutes of Health
Arul M. Chinnaiyan: University of Michigan Medical School
Warren J. Leonard: National Institutes of Health
Shaomeng Wang: University of Michigan Medical School
Weiping Zou: University of Michigan Medical School

Nature, 2025, vol. 643, issue 8071, 519-528

Abstract: Abstract Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell–transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.

Date: 2025
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DOI: 10.1038/s41586-025-09000-3

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