BMP9 potentiates immunotherapy in triple-negative breast cancer by suppressing Tregs infiltration via the PRKDC-CCL2 axis

作者：Yiqing You, Lan Wei, Meng Dai, Guozhi Zhao, Kun Fan, Tingting Dang, Haoli Sun, Liang Zhang, Qian Li, Mengxin Sun, Xiaolu Li, Xiran He, Shiyu Yang, Tao Zeng, Jiafeng Tang, Yan Zhang · 发表于：Cancer Letters · 年份：2025 · DOI：10.1016/j.canlet.2025.218175 · 被引用次数：5 · 研究领域：TGF-β signaling in diseases、Cancer Cells and Metastasis、Bone Metabolism and Diseases

Immunotherapy represents a pivotal strategy for triple-negative breast cancer (TNBC), yet its efficacy is constrained by the immunosuppressive tumor microenvironment (TME). In this study, we demonstrate that bone morphogenetic protein-9 (BMP9) inhibits tumor growth and reprograms the immune TME in orthotopic TNBC models, primarily by attenuating regulatory T cells (Tregs) infiltration. Tregs depletion abrogates si-BMP9-mediated tumor promotion. Mechanistically, BMP9 suppresses CCL2 expression in an exocrine-independent manner to restrict Tregs recruitment. We identify DNA-dependent protein kinase catalytic subunit (PRKDC) as a BMP9-binding transcriptional regulator. The interaction between PRKDC and BMP9 directly impedes CCL2 transcriptional activation by suppressing PRKDC phosphorylation and indirectly suppresses CCL2 expression via NF-κB pathway remodeling. Critically, BMP9 modulation and CCL2 targeting potentiates immunotherapy efficacy without observable toxicity. Our study unveils the BMP9-PRKDC-CCL2 axis as a master regulatory node for TNBC-Tregs crosstalk, providing a strategy to overcome immunotherapy resistance in TNBC.