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巨细胞NLRP3激活和IL-1β释放驱动 osimertinib诱导的抗瘤免疫

Haiyang Yu¹, Xin Sun², Yan Li^1,3

¹Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Journal for immunotherapy of cancer

|October 6, 2025

概括

奥西默提尼布激活了巨细胞中的NLRP3炎症酶,增强了非小细胞肺癌 (NSCLC) 的抗瘤免疫力. 这一发现表明,瘤相关巨细胞 (TAMs) 中的NLRP3炎症酶激活和IL-1β是EGFR-TKI疗效的预测生物标志物.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
细胞生物学细胞生物学

背景情况:

皮表皮生长因子受体氨酸激酶抑制剂 (EGFR-TKIs) 在非小细胞肺癌 (NSCLC) 中显示出临床疗效,但患者的结果各不相同.
驱动这些可变反应的精确机制,即使在具有相同EGFR突变的患者中,仍然不完全理解.

研究的目的:

调查第三代EGFR-TKI的osimertinib是否激活了巨细胞中的核酸结合寡聚化域类受体蛋白-3 (NLRP3) 炎症体.
探索奥西默提尼布诱导的NLRP3炎症酶激活的机制基础及其在驱动抗瘤免疫力中的作用.
评估NLRP3炎症酶激活和IL-1β在接受EGFR-TKI治疗的NSCLC患者中的临床相关性.

主要方法:

利用骨髓衍生的巨细胞,人体外围血液单核细胞和易斯肺癌小鼠模型来评估奥西默蒂尼布诱导的NLRP3炎症酶激活,IL-1β分泌和热.
研究的机制性途径包括溶酶体功能障碍,过载,线粒体损伤和反应性氧物种 (ROS) 生产.
与接受EGFR-TKI治疗的NSCLC患者的临床数据相关的发现.

主要成果:

奥西默提尼布通过 lysosomal 功能障碍激活了巨细胞中的 NLRP3 炎症酶,导致过载,线粒体损伤和 ROS 生产.
这种激活促进了IL-1β释放,热和CD8+T细胞激活,同时抑制了瘤微环境中的调节性T细胞.
在体内, osimertinib 的抗瘤作用依赖于 NLRP3 炎症酶激活,并因 IL-1β 联合使用而增强;高NLRP3 和 IL-1β 瘤相关巨细胞 (TAM) 的高NLRP3 和 IL-1β 表达与 EGFR-TKI 治疗的 NSCLC 患者中改善的无进展和整体存活相关.

结论:

奥西默提尼布通过激活NLRP3炎症体来表现出非标免疫调节作用,将线粒体-溶酶体交叉连接到增强的抗瘤免疫力.
在TAM中NLRP3炎症酶和IL-1β作为EGFR-TKI疗效的预测生物标志物.
与IL-1β的联合治疗可能是改善NSCLC临床结果的新策略.

关键词:

细胞因子细胞因子免疫调节器免疫调节器肺癌肺癌是一种肺癌.巨细胞是一个巨细胞.瘤微环境 - - 瘤微环境

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