Fan Guanglin, Zuo Shuting, Wang Zhen, Zhang Siwei, Liu Liping, Luo Haoge, Xie Yingdong, Zhang Yan, Li Dong
Department of Breast Surgery, The Second Hospital of Jilin University, Changchun, People's Republic of China.
Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
Sci Rep. 2025 May 25;15(1):18172. doi: 10.1038/s41598-025-03260-9.
Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murine models (orthotopic 4T1 and spontaneous MMTV-PyMT). Elevated IL-33 levels correlated with aggressive subtypes and poor prognosis. IL-33 overexpression enhanced proliferation, migration, and cancer stem cell (CSC) marker expression (CD44, ALDH1) in 4T1 and MDA-MB-231 cells, whereas ST2 knockdown via CRISPR or adeno-associated virus (AAV) attenuated tumor growth and metastasis in vivo, reducing CSC frequency. Mechanistically, IL-33 activated Wnt/β-catenin signaling to promote stemness, which was reversed by the Wnt inhibitor XAV-939. Single-cell analysis revealed that IL-33 overexpression skewed the immune microenvironment toward immunosuppression, while ST2 knockdown restored antitumor immunity. Our findings establish an IL-33-Wnt axis as a critical driver of breast cancer aggressiveness and propose AAV-mediated ST2 silencing as a novel therapeutic strategy. Targeting this axis may offer dual benefits by suppressing stemness and enhancing immune surveillance, warranting clinical exploration for advanced breast cancer.
白细胞介素-33（IL-33）在肿瘤进展中发挥多方面作用，但其通过Wnt通路对乳腺癌干性和转移的自分泌调节仍不清楚。在此，我们使用CRISPR/Cas9、单细胞RNA测序和小鼠模型（原位4T1和自发的MMTV-PyMT）研究了乳腺癌中的IL-33/ST2轴。IL-33水平升高与侵袭性亚型和不良预后相关。IL-33过表达增强了4T1和MDA-MB-231细胞的增殖、迁移及癌症干细胞（CSC）标志物表达（CD44、ALDH1），而通过CRISPR或腺相关病毒（AAV）敲低ST2可在体内减弱肿瘤生长和转移，降低CSC频率。机制上，IL-33激活Wnt/β-连环蛋白信号以促进干性，这被Wnt抑制剂XAV-939逆转。单细胞分析显示，IL-33过表达使免疫微环境向免疫抑制倾斜，而敲低ST2可恢复抗肿瘤免疫。我们的研究结果确立了IL-33-Wnt轴是乳腺癌侵袭性的关键驱动因素，并提出AAV介导的ST2沉默作为一种新的治疗策略。靶向该轴可能通过抑制干性和增强免疫监视带来双重益处，值得对晚期乳腺癌进行临床探索。
