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, Yu-Rui Chen, Kai Lu, Chunyan Chu, Chuanjun Shu, Yue Hou, Yang Xue, Naipeng Shi, Zhijun Chen, Lihua Zhang, Lei Zhang, Rong Na, Ming Chen, Shenghong Ju, Dingxiao Zhang, Yi Ma, Bin Xu
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. Immune check point therapies have not been successful for prostate cancers, but the underlying mechanisms are unclear. Here the authors show that a transcription factor, YY1, may promote the SUMOylation and stability of HIF-1α to suppress anti-tumor immunity, while targeting YY1 helps improve tumor control, in mouse prostate cancer models.