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; Weiping Zou

doi:10.1038/s41586-025-09000-3

STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity

Nature. 2025 Jul;643(8071):519-528. doi: 10.1038/s41586-025-09000-3. Epub 2025 May 14.

Authors

Jiajia Zhou^{1

2}, Kole Tison^{1

2

3

4}, Haibin Zhou⁵, Longchuan Bai⁵, Ranjan Kumar Acharyya⁵, Donna McEachern⁵, Hoda Metwally⁵, Yu Wang⁵, Michael Pitter^{1

2}, Jae Eun Choi^{6

7}, Linda Vatan^{1

2}, Peng Liao^{1

2}, Jiali Yu^{1

2}, Heng Lin^{1

2}, Long Jiang^{2

4}, Shuang Wei^{1

2}, Xue Gao^{1

2}, Sara Grove^{1

2}, Abhijit Parolia^{6

7}, Marcin Cieslik^{4

6

7}, Ilona Kryczek^{1

2}, Michael D Green^{2

8}, Jian-Xin Lin⁹, Arul M Chinnaiyan^{6

7

10

11

12}, Warren J Leonard⁹, Shaomeng Wang^{13

14

15

16

17}, Weiping Zou^{18

19

20

21

22

23}

Affiliations

¹ Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
² Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
³ Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
⁶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁷ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁸ Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁹ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
¹¹ University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
¹² Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA.
¹³ Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. shaomeng@umich.edu.
¹⁴ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. shaomeng@umich.edu.
¹⁵ University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
¹⁶ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA. shaomeng@umich.edu.
¹⁷ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
¹⁸ Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. wzou@umich.edu.
¹⁹ Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. wzou@umich.edu.
²⁰ Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. wzou@umich.edu.
²¹ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. wzou@umich.edu.
²² University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. wzou@umich.edu.
²³ Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA. wzou@umich.edu.

Abstract

Immune checkpoint blockade (ICB) has transformed cancer therapy^1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation^3,4. 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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line, Tumor
Dendritic Cells* / cytology
Dendritic Cells* / drug effects
Dendritic Cells* / immunology
Dendritic Cells* / metabolism
Female
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immunotherapy
Janus Kinase 2 / metabolism
Male
Mice
Mice, Inbred C57BL
Neoplasms* / immunology
Neoplasms* / pathology
Neoplasms* / therapy
Proteolysis / drug effects
STAT3 Transcription Factor* / antagonists & inhibitors
STAT3 Transcription Factor* / metabolism
STAT5 Transcription Factor* / antagonists & inhibitors
STAT5 Transcription Factor* / genetics
STAT5 Transcription Factor* / metabolism
Signal Transduction
T-Lymphocytes / immunology
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology

Substances

STAT3 Transcription Factor
STAT5 Transcription Factor
Immune Checkpoint Inhibitors
Janus Kinase 2
Stat3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding