Abstract：
The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
摘要：
前列腺癌（PCa）的肿瘤微环境（TME）的特征是高水平的免疫抑制分子，包括细胞因子和趋化因子。这产生了阻碍有效免疫反应的敌对免疫景观。白细胞介素-1（IL-1）受体拮抗剂（IL1RN），一个关键的抗炎分子，在抑制IL-1相关的免疫和炎症反应中起重要作用。我们的研究调查了IL1RN在PCa中的致癌作用，特别是它与毒蕈碱乙酰胆碱受体4（CHRM4）的相互作用，及其参与驱动PCaTME内的免疫抑制途径和M2样巨噬细胞极化。我们证明在雄激素剥夺治疗(ADT)之后，PCa中IL1RN-CHRM4相互作用激活MAPK/AKT信号通路。这种激活上调转录因子E2F1和MYCN，刺激IL1RN的产生，并创建一个正反馈回路，增加PCa细胞和M2样巨噬细胞中CHRM4的丰度。这种ADT驱动的IL1RN/CHRM4轴显着增强与神经内分泌分化和治疗抗性结果相关的免疫检查点标记。在晚期PCa患者中，较高的血清IL1RN水平与疾病侵袭性和M2样巨噬细胞标志物增加相关。此外,IL1RN水平升高与免疫治疗后更好的临床结局相关.在晚期PCa患者和神经内分泌PCa类器官模型中IL1RN和CHRM4表达之间的临床相关性突出了它们作为治疗靶标的潜力。我们的数据表明，靶向IL1RN/CHRM4信号可能是管理PCa进展和增强治疗反应的有希望的策略。
