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PIKfyve 抑制诱导抗瘤免疫因子性通过减轻 STING 贩运和溶酶体退化

Jie He^1,2,3,4, Rui Huang^1,2,4, Chunyan Zong^1,2,4

¹Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cancer immunology research

|May 22, 2025

概括

抑制PIKfyve通过促进IFN基因 (cGAS-STING) 循环GMP-AMP合成酶刺激通路来增强癌症免疫疗法. 这种方法改善了对抗PD-1疗法等现有治疗方法的反应.

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:

免疫检查点封锁在癌症治疗中表现有前途,但在反应率方面存在局限性.
激活IFN基因 (cGAS-STING) 循环GMP-AMP合成酶刺激器通路对于对瘤的先天免疫反应至关重要.
需要新的组合策略来提高癌症免疫疗法的疗效.

研究的目的:

为了确定cGAS-STING信号通路的新型调节器.
探索PIKfyve作为增强抗瘤免疫力的潜在治疗标.
评估PIKfyve抑制与现有的癌症疗法结合使用的疗效.

主要方法:

利用了连接地图数据库和激酶抑制剂图书馆屏幕.
评估了IFN刺激基因的功能读数.
通过使用遗传学和药理学方法,研究了PIKfyve在STING贩运和退化中的作用.
在黑色素瘤和B16F10瘤模型中评估治疗疗效.

主要成果:

确定了PIKfyve作为cGAS-STING信号的负调节器.
通过YM201636或基因切除抑制PIKfyve,上调IFN刺激基因和招募CD8+T淋巴细胞.
抑制PIKfyve使黑色素瘤对西斯普拉丁和抗PD-1联合治疗敏感,从而产生持久的反应.
STING和CD8+T细胞枯竭减少了协同效应,证实了该机制.

结论:

PIKfyve通过促进STING lysosomal降解来负面调节cGAS-STING信号传递.
抑制PIKfyve增强了抗瘤免疫反应,并提高了组合免疫疗法的疗效.
准PIKfyve是一个有希望的策略,可以增强STING信号和改善癌症治疗结果.

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