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抑制DPP9通过干扰清细胞脏细胞癌中的BRISC介导PD-L1表达来增强抗瘤免疫力

Wei Zhang¹, Yue Wang^2,3, Tao Feng^2,3

¹Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Cell death and differentiation

|March 14, 2026

概括

研究人员发现,二乙酶9 (DPP9) 调节了清细胞细胞癌 (ccRCC) 中的PD-L1. 用1G244抑制DPP9恢复了抗瘤免疫力,并增强了ccRCC的免疫疗法.

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:

针对PD-1/PD-L1的免疫检查点阻塞疗法对于清细胞细胞癌 (ccRCC) 治疗至关重要.
初级耐药性和免疫逃避限制了ccRCC目前免疫疗法的疗效.

研究的目的:

在ccRCC中识别PD-L1表达的新型调节剂.
探索DPP9抑制作为一种治疗策略,以增强ccRCC免疫疗法.

主要方法:

研究了dpeptidyl peptidase 9 (DPP9) 在ccRCC PD-L1调控中的作用.
通过化合物1G244.4利用DPP9的药理抑制.
阐明了涉及BRISC-SHMT2复合体和IFNAR1.1的分子机制.
在组合治疗模型中评估T细胞细胞毒性和抗瘤免疫力.

主要成果:

DPP9被确定为ccRCC中PD-L1表达的关键调节者.
通过1G244抑制DPP9,恢复了T细胞细胞毒性和改善了检查点阻断的有效性.
DPP9抑制通过破坏DPP9-SHMT2相互作用并促进IFNAR1降解来逆转PD-L1上调.
与1G244和抗CTLA-4的联合治疗表明增强了抗瘤免疫力.

结论:

定义了一个控制PD-L1转录的新型DPP9-BRISC-SHMT2调节轴.
1G244代表了一种潜在的治疗剂,可以增强ccRCC中癌症免疫治疗的疗效.

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