SPOP（Speckle-type POZ蛋白）在DNA损伤应答（DDR）和基因组稳定性维持中起着重要作用。在多达15％的前列腺癌中发现了SPOP1底物结合槽的体细胞杂合错义突变。尽管SPOP突变可预测雄激素受体信号抑制（ARSi）治疗的益处，但SPOP突变型（SPOPmut）前列腺癌患者的预后多样化，缺乏针对SPOPmut去势抵抗前列腺癌（CRPC）的靶向治疗。利用体外基因组和转录组肿瘤数据、蛋白质组学分析和基因修饰细胞系模型，我们展示了SPOP突变、STING信号通路改变和PARP抑制剂敏感性之间的机制联系。我们证明SPOP突变与29种非经典（NC）STING1（NC-STING）基因组标记上调有关，该标记存在于一部分SPOPmut、难治性CRPC患者中。我们在临床前CRPC模型中展示了SPOP靶点破坏和不稳定STING蛋白，前列腺癌相关SPOP突变导致了上调的NC-STING-NF-κB信号通路和宏噬细胞及肿瘤微环境（TME）促进重编程，从而导致肿瘤细胞生长。重要的是，我们提供了体外和体内机制为基础的证据，表明PARP抑制剂（PARPi）治疗导致NC-STING-NF-κB信号向抗肿瘤的正统cGAS-STING-IFN-β信号的转变，从而增强了对SPOPmut CRPC的肿瘤生长抑制。我们提供了证据表明，SPOP在调节DNA损伤诱导的前列腺癌STING活化所致的免疫抑制与抗肿瘤活性方面发挥关键作用。SPOPmut CRPC的PARPi治疗改变了这种NC-STING信号通路，向正统的抗肿瘤cGAS-STING-IFN-β信号通路转变，突显了一种针对前列腺癌的新型生物标志物导向的治疗策略。

Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP1 substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, outcomes for patients with SPOP-mutant (SPOPmut) prostate cancer are heterogeneous and targeted treatments for SPOPmut castrate-resistant prostate cancer (CRPC) are lacking.Using in silico genomic and transcriptomic tumor data, proteomics analysis and genetically modified cell line models we demonstrate mechanistic links between SPOP mutations, STING signaling alterations and PARP inhibitor vulnerabilities.We demonstrate that SPOP mutations are associated with upregulation of a 29-gene non-canonical (NC) STING1 (NC-STING) signature in a subset of SPOPmut, treatment-refractory CRPC patients. We show in preclinical CRPC models that SPOP targets and destabilizes STING protein, and prostate cancer ̶ associated SPOP mutations result in upregulated NC-STING-NF-κB signaling and macrophage- and tumor microenvironment (TME)-facilitated reprogramming, leading to tumor cell growth. Importantly, we provide in vitro and in vivo mechanism-based evidence that PARP inhibitor (PARPi) treatment results in a shift from immunosuppressive NC-STING-NF-κB signaling to anti-tumor, canonical cGAS-STING-IFN-β signaling in SPOPmut CRPC and results in enhanced tumor growth inhibition.We provide evidence that SPOP is critical in regulating immunosuppressive versus anti-tumor activity downstream of DNA damage-induced STING activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, anti-tumor cGAS-STING-IFN-β signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.