Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.

慢性炎症和免疫抑制微环境促进前列腺癌 (PCa) 进展并降低对免疫检查点阻断 (ICB) 疗法的反应。然而，目前尚不清楚这两个事件是如何以及在多大程度上协调的。在这里，我们表明 ARID1A 是 SWI/SNF 染色质重塑复合物的一个亚基，它在炎症诱导的 IKKβ 激活下游发挥作用，以塑造免疫抑制性肿瘤微环境 (TME)。Arid1a的前列腺特异性缺失与Pten 缺失协同作用以加速前列腺肿瘤发生。我们将多形核髓源性抑制细胞 (PMN-MDSCs) 鉴定为导致免疫逃避的主要浸润性免疫细胞类型，并揭示 PMN-MDSCs 的中和作用限制了Arid1a 缺陷肿瘤。从机制上讲，炎症信号激活 IKKβ 以磷酸化 ARID1A，导致其通过 β-TRCP 降解。ARID1A 下调反过来会沉默 A20 去泛素化酶的增强子，A20去泛素化酶是 NF-κB 信号的关键负调节因子，从而释放 CXCR2 配体介导的 MDSC 趋化性。重要的是，我们的结果支持抗 NF-κB 抗体或靶向 CXCR2 联合 ICB 治疗晚期 PCa 的治疗策略。总之，我们的研究结果强调 IKKβ/ARID1A/NF-κB 反馈轴整合了炎症和免疫抑制以促进 PCa 进展。