恩扎卢胺是一种下一代抗雄激素剂，已获批用于治疗转移性去势抵抗性前列腺癌（CRPC）。尽管恩扎卢胺已被证明可以改善CRPC患者的进展时间并延长总生存期，但大多数患者最终会对治疗产生抵抗。免疫疗法在这类患者中的临床效益有限；了解抵抗机制有助于开发新的更有效的CRPC治疗方法。肿瘤抵抗各种治疗方法的机制之一是肿瘤表型可塑性，即癌细胞获得间质特征，有时还伴有典型上皮特征的丧失。本研究探讨了恩扎卢胺耐药性、肿瘤表型可塑性和前列腺癌对免疫介导的溶解抵抗之间的潜在联系。 通过长期将人类前列腺癌细胞系暴露于培养液中的恩扎卢胺，建立了对恩扎卢胺耐药的前列腺癌模型。评估了体外和体内肿瘤细胞的表型特征，以及对免疫效应细胞介导的细胞毒作用的敏感性。 恩扎卢胺耐药与肿瘤获得间质特征、雌激素受体表达增加以及明显降低肿瘤对自然杀伤（NK）细胞介导的溶解作用的敏感性相关。这种效应与恩扎卢胺耐药细胞与NK细胞结合形成减少有关。雌激素受体选择性降解剂富维司汀可以恢复靶细胞与NK细胞结合的形成，并增加体外NK细胞的溶解作用。体内，富维司汀对恩扎卢胺耐药细胞显示了抗肿瘤活性，这种效应与NK细胞的激活有关。 NK细胞正在成为前列腺癌中有望的治疗方法。通过使用富维司汀阻断雌激素受体来改变肿瘤可塑性，可以为恩扎卢胺耐药性CRPC中基于NK细胞的免疫干预提供机会。 © 作者（或其雇主）2023年刊行。在CC BY-NC下允许再利用。无商业再利用。请参阅权利和权限。由BMJ发布。

Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer.Models of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity.Resistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells.NK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.