长期接受雄激素剥夺疗法（ADT）治疗后，几乎不可避免地会发生去势抵抗性前列腺癌（CRPC），导致显着的死亡率。研究驱动 CRPC 发展的机制势在必行。在这里，我们确定了在 CRPC 患者中频繁扩增的先锋转录因子 GATA2 抑制干扰素 (IFN)-β 介导的抗肿瘤免疫，从而促进 CRPC 进展。采用基因工程小鼠模型 (GEMM)，我们证明 GATA2 过表达阻碍去势诱导的细胞凋亡和肿瘤缩小，促进肿瘤转移和 CRPC 发展。值得注意的是，GATA2 主要通过抑制去势诱导的 IFN-β 信号激活和 CD8 T 细胞浸润来驱动去势抵抗。这一发现与 CRPC 患者中 GATA2 表达和 IFNB1 表达以及 CD8 T 细胞浸润之间的负相关相一致。从机制上讲，GATA2 招募 PIAS1 作为辅抑制子，并以不依赖雄激素的方式重新编程 IFN-β 轴的关键转录因子 IRF3 的顺反子。此外，我们还发现了一种新型沉默元件，它通过环向 IFNB1 启动子来促进 GATA2 和 PIAS1 的功能。重要的是，GATA2 的消耗增强了抗肿瘤免疫力并减弱了 CRPC 的发展。因此，我们的研究结果阐明了一种新机制，其中 GATA2 通过抑制 IFN-β 轴介导的抗肿瘤免疫来促进 CRPC 进展，强调 GATA2 作为 CRPC 的一个有前景的治疗靶点。© 2024。作者获得 Springer Nature Limited 的独家许可。

Castration-resistant prostate cancer (CRPC) nearly inevitably develops after long-term treatment with androgen deprivation therapy (ADT), leading to significant mortality. Investigating the mechanisms driving CRPC development is imperative. Here, we determined that the pioneer transcription factor GATA2, which is frequently amplified in CRPC patients, inhibits interferon (IFN)-β-mediated antitumor immunity, thereby promoting CRPC progression. Employing a genetically engineered mouse model (GEMM), we demonstrated that GATA2 overexpression hindered castration-induced cell apoptosis and tumor shrinkage, facilitating tumor metastasis and CRPC development. Notably, GATA2 drives castration resistance predominantly via repressing castration-induced activation of IFN-β signaling and CD8+ T-cell infiltration. This finding aligns with the negative correlation between GATA2 expression and IFNB1 expression, as well as CD8+ T-cell infiltration in CRPC patients. Mechanistically, GATA2 recruited PIAS1 as corepressor, and reprogramed the cistrome of IRF3, a key transcription factor of the IFN-β axis, in an androgen-independent manner. Furthermore, we identified a novel silencer element that facilitated the function of GATA2 and PIAS1 through looping to the IFNB1 promoter. Importantly, depletion of GATA2 augmented antitumor immunity and attenuated CRPC development. Consequently, our findings elucidate a novel mechanism wherein GATA2 promotes CRPC progression by suppressing IFN-β axis-mediated antitumor immunity, underscoring GATA2 as a promising therapeutic target for CRPC.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.