雄性的耐抗性前列腺癌（CRPC）与不良预后和治疗相关不良反应的风险提高有关，全球癌症死亡率也较高。因此，有必要探索具有双重治疗和生物标志物功能的新型潜在分子。根据最近的研究发现，与激素依赖型前列腺癌（PC）患者相比，CRPC患者前列腺癌（PC）组织中ATM（ataxia telangiectasia mutant kinase）的表达水平更高。使用CRPC细胞系（C4-2和CWR22Rv1），转移室实验表明ATM通过C-X-C蛋白因子化学趋化因子12（CXCL12）在体外增加了CRPC细胞的巨噬细胞招募。进一步的体外研究证明，极化的巨噬细胞阻止了NK细胞的招募，并减少了NK细胞对CRPC细胞系的免疫杀伤活性。此外，ATM通过PI3K/AKT信号通路，在选择的细胞系中增加了PD-L1（programmed death receptor ligand 1）的表达，同时抑制了NK群2D（NKG2D）配体的表达。体内研究表明，ATM促进了CRPC和巨噬细胞的增殖，而NK细胞的招募被发现可以抑制ATM的表达和CRPC的增殖。总之，我们证明抑制ATM通过阻尼CXCL12和PI3K/AKT-PD-L1途径增加了CRPC对NK细胞抑制剂的易感性，从而为治疗CRPC提供了新的个体化治疗方案。

Castration-resistant prostate cancer (CRPC) in males is associated with a poor prognosis and a higher risk of treatment-related adverse effects, with high mortality among cancers globally. It is thus imperative to explore novel potential molecules with dual therapeutic and biomarker functions. Based on the recent research findings, the expression levels of ataxia telangiectasia mutant kinase (ATM) in prostate cancer (PC) tissues collected from CRPC patients were higher than hormone-dependent PC patients. Using CRPC cell lines (C4-2 and CWR22Rv1), the transwell chamber experiments revealed ATM promoted macrophage recruitment in CRPC cells in vitro via C-X-C motif chemokine ligand 12 (CXCL12). Further in vitro investigations demonstrated that polarized macrophages prevented NK cell recruitment and reduced the immunocidal activity of NK cells against CRPC cell lines. Moreover, ATM boosted programmed death receptor ligand 1 (PD-L1) expression while inhibiting NK group 2D (NKG2D) ligand expression in selected cell lines via PI3K/AKT signaling pathway. The in vivo investigations revealed ATM induced proliferation of CRPC and macrophage recruitment, while the NK cell recruitment was found to suppress ATM expression and CRPC proliferation. In conclusion, it could be demonstrated that inhibiting ATM increased the susceptibility of CRPC to NK cell inhibitors by dampening the CXCL12 and PI3K/AKT-PD-L1 pathways, thereby offering a novel and individualized treatment protocol for treating CRPC.