库库比他B通过共价向MTCH2刺激恶性乳腺癌中的PD-1免疫疗法反应
Qianqian Xu1, Zeyu Jiang1, Yuqi Pan1
1College of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue No. 138, Nanjing, Jiangsu, 210046, PR China; China Jiangsu Key Laboratory of Research and Development in Marine Bio-resource Pharmaceutics, Xianlin Avenue No. 138, Nanjing, Jiangsu, 210046, PR China.
概括
库库比他B (CuB) 向线粒体蛋白MTCH2,增强乳腺癌免疫疗法. 这种机制激活了天生的免疫力,在临床前模型中提高了PD-1阻断的有效性.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 恶性乳腺癌需要新的治疗方法,因为耐药性和免疫抑制性瘤微环境限制了PD-1阻断的有效性.
- 天然产品Cucurbitacin B (CuB) 显示有可能使乳腺癌对PD-1免疫疗法的敏感,但其机制尚不清楚.
研究的目的:
- 在乳腺癌中确定CuB的直接分子标.
- 阐明CuB与PD-1阻塞疗法的协同作用的机制.
主要方法:
- 定量醇反应性分析 (QTRP) 确定了CuB结合蛋白.
- 通过微尺度热泳 (MST),细胞热转移试验 (CETSA) 和基于活动的蛋白质分析 (ABPP) 验证的结合.
- 在试验室,外生和侵袭性乳腺癌的体内模型中评估的功能性结果.
主要成果:
- 立方体直接和共地准线粒体外膜蛋白MTCH2,该蛋白在侵袭性乳腺癌中表达过度.
- 由CuB诱导的MTCH2中断导致线粒体功能障碍,线粒体DNA (mtDNA) 释放,并随后激活cGAS-STING先天免疫路径.
- 这种激活导致I型干扰素产生,中性粒细胞激活,增强抗瘤免疫力,并在临床前模型中与PD-1阻断产生协同效果.
结论:
- CuB通过共同向MTCH2来增强抗瘤免疫力,诱导线粒体功能障碍和cGAS-STING通路激活.
- MTCH2被确定为线粒体功能和瘤免疫性之间的关键联系.
- 研究结果支持将CuB或MTCH2调节器与PD-1阻断结合起来,用于恶性乳腺癌治疗.
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