准美瓦酸途径增强了NUAK1抑制诱导的免疫细胞死亡和抗瘤免疫力
Liming Gui1, Kaiwen Chen1, Jingjing Yan1
1Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
抑制NUAK1激酶通过增加活性氧物种 (ROS) 来促进癌细胞死亡和瘤抑制. 用他类药物准美瓦酸途径会放大这种效果,增强免疫治疗的疗效.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 免疫性细胞死亡 (ICD) 是一种有前途的癌症疗法,但需要优化.
- 确定NUAK1激酶是诱导ICD的新目标.
研究的目的:
- 探索NUAK1抑制以增强ICD和抗瘤免疫力.
- 调查梅瓦酸途径在ICD调节中的作用.
主要方法:
- 全基因组的CRISPR-Cas9查,以确定治疗点.
- 研究活性氧物种 (ROS) 生产和NRF2通路调节.
- 使用CRISPR淘汰和HMGCR抑制剂 (西姆瓦斯塔丁) 来准美酸盐路径.
主要成果:
- 抑制NUAK1通过ROS产生的ICD诱导,与NRF2下调相关.
- 由XBP1s激活的美酸盐通路对ICD产生负面反.
- 用他类药物或CRISPR向美酸盐途径可以放大NUAK1抑制诱导的ICD和抗瘤效应.
- 胆固醇抑制ROS和ICD,阻碍了瘤的抑制.
结论:
- 阻断美酸盐-胆固醇通路可以增强NUAK1抑制介导的ICD.
- 将NUAK1抑制与他类药物结合起来,可以提高抗PD-1疗法的疗效.
- 这一策略为ICD向的癌症免疫疗法提供了一个有前途的方法.
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