YY1 enhances HIF-1α stability in tumor-associated macrophages to suppress anti-tumor immunity of prostate cancer in mice

Wenchao Li, SaiSai Chen, Jian Lu, Weipu Mao, Shiya Zheng, Minhao Zhang, Tiange Wu, Yurui Chen, Kai Lu, Chunyan Chu, Chuanjun Shu, Yue Hou, Xue Yang, Naipeng Shi, Zhijun Chen, Lihua Zhang, Lei Zhang, Rong Na, Ming Chen, Shenghong Ju (), Dingxiao Zhang (), Yi Ma () and Bin Xu ()
Additional contact information
Wenchao Li: Southeast University
SaiSai Chen: Southeast University
Jian Lu: Southeast University
Weipu Mao: Southeast University
Shiya Zheng: Southeast University
Minhao Zhang: Xishan People’s Hospital of Wuxi City
Tiange Wu: Southeast University
Yurui Chen: Southeast University
Kai Lu: Southeast University
Chunyan Chu: Southeast University
Chuanjun Shu: Nanjing Medical University
Yue Hou: Xi’an Jiaotong University
Xue Yang: Southeast University
Naipeng Shi: Northern Jiangsu People’s Hospital
Zhijun Chen: The First Affiliated Hospital of Bengbu Medical University
Lihua Zhang: Southeast University
Lei Zhang: Southeast University
Rong Na: The University of Hong Kong
Ming Chen: Southeast University
Shenghong Ju: Southeast University
Dingxiao Zhang: Hunan University
Yi Ma: China Pharmaceutical University
Bin Xu: Southeast University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Immune checkpoint therapy for prostate cancer (PCa), a classic ‘immune-cold’ tumor characterized by an immunosuppressive tumor microenvironment, failed previously in clinical trials, but the underlying causes remain elusive. Here we find that YY1+, immunosuppressive macrophages aggregate in the hypoxic areas of PCa. Mechanistically, hypoxia promotes the phase separation of YY1 in the nucleus, where YY1 binds to NUSAP1 and promotes the SUMOylation, phase separation and stabilization of HIF-1α. Either myeloid-specific conditional knockout of YY1 or a treatment with tenapanor for decreasing the YY1–NUSAP1–HIF-1α interaction impairs subcutaneous PCa tumor formation in mouse prostate tumor models. Lastly, a first-generation tetrahedral DNA nanostructure based on the proteolysis targeting chimera technique, termed YY1-DcTAC, allows targeting and degrading YY1 in tumor-associated macrophages for inducing antitumor effects and CD8+ T cell tumor infiltration in mouse tumor models. In summary, our findings underscore the pivotal role of YY1 in the hypoxia/HIF-1α pathway in tumor-associated macrophages and support the targeting of YY1 for treating PCa.

Date: 2025
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DOI: 10.1038/s41467-025-61560-0

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