Nuclear PD-L1 drives IFN-γ-promoted lung metastasis of triple-negative breast cancer via POLR2A-mediated transcriptional activation of LY6E

作者：Xu Wang, Qi Zhou, Pu Wang, Shunshun Bao, Xianzheng Wei, Xuan Zhao, Rui Hou, Sijin Li, Zhangchun Guan, Wen Ma, Junnian Zheng, Dan Liu, Ming Shi · 发表于：Breast Cancer Research · 年份：2025 · DOI：10.1186/s13058-025-02193-5 · 被引用次数：2 · 研究领域：Cancer Immunotherapy and Biomarkers、Inflammasome and immune disorders、NF-κB Signaling Pathways

BACKGROUND: Triple-negative breast cancer (TNBC) patients exhibiting high PD-L1 expression demonstrate poor responses to anti-PD-L1 therapy and aggressive lung metastasis. The paradoxical role of PD-L1 beyond its immune checkpoint function and the impact of interferon-γ-secreted during immunotherapy-on metastasis remain poorly understood. METHODS: Integrated reanalysis of single-cell RNA sequencing (scRNA-seq) data from TNBC lung metastases identified enriched signaling pathways. IFN-γ function was assessed using murine and human TNBC cell lines, employing in vitro assays and in vivo modeling in both immunocompetent and immunodeficient mice. CRISPR/Cas9-mediated PD-L1 ablation, pharmacological inhibitors, RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (Co-IP), bioinformatics analyses, and in vivo metastasis assays were utilized to dissect underlying mechanisms. RESULTS: scRNA-seq revealed significant enrichment of IFN-γ signaling within a distinct metastatic TNBC cluster. IFN-γ pretreatment potently enhanced the lung metastatic capacity of TNBC cells in both immunocompetent and immunodeficient murine models. CRISPR/Cas9-mediated PD-L1 ablation abolished IFN-γ-driven metastasis without affecting proliferation, indicating an immune checkpoint-independent mechanism. Mechanistically, IFN-γ facilitated HDAC2-mediated deacetylation of PD-L1, promoting its nuclear translocation. RNA-seq identified lymphocyte antigen 6 complex lo...