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.
Nature communications. 2025 Jul 07*** epublish ***
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, Bin Xu
Department of Urology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China., Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China., Department of Oncology, Zhongda Hospital, Southeast University, Nanjing, China., Department of Urology, Xishan People's Hospital of Wuxi City, Wuxi, China., Department of Pathology, Zhongda Hospital, Southeast University, Nanjing, China., Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China., Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China., Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China., Department of Urology, Northern Jiangsu People's Hospital, Yangzhou, China., Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China., Department of Surgery, LKS School of Medicine, The University of Hong Kong, Hong Kong, China., Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China. ., School of Biomedical Sciences, Hunan University, Changsha, China. ., Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, China. ., Department of Urology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China. .