与癌症相关的脂肪细胞通过FGF21驱动的脂解调解CD8+T细胞功能障碍
Sumiya Dalangood1, Cegui Hu1, Chenwei Yuan2
1State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Cell reports
|November 5, 2025
概括
与癌症相关的脂肪细胞释放脂肪酸,从而损害瘤中CD8+ T细胞的功能. 针对由FGF21和ATGL驱动的这种脂解,恢复T细胞活性并增强癌症免疫疗法.
科学领域:
- 癌症生物学 癌症生物学
- 免疫学 免疫学 免疫学
- 代谢研究的研究.
背景情况:
- 癌症相关脂肪细胞 (CAAs) 影响瘤微环境 (TME).
- CAA与CD8+T细胞之间的代谢相互作用尚未完全理解.
- CD8+ T 细胞对于抗瘤免疫是至关重要的.
研究的目的:
- 为了研究CAAs和CD8+T细胞之间的代谢交叉.
- 确定CAAs影响CD8+T细胞功能的机制.
- 探索针对癌症免疫治疗的CAA代谢的治疗策略.
主要方法:
- 研究CAA中的脂解及其对CD8+T细胞的影响.
- 使用FGF21删除模型和ATGL抑制.
- 评估了线粒体平衡和CD8+T细胞的效应器功能.
- 评估瘤生长和对抗PD-1疗法的反应.
主要成果:
- CAA通过脂解释放自由脂肪酸,导致CD8+T细胞的脂质过氧化和线粒体功能障碍,导致疲劳.
- 通过FGFR1/KLB-p38信号传递,FGF21通过上调ATGL来促进CAA脂解.
- 删除FGF21或抑制ATGL恢复了CD8+T细胞功能,并抑制了瘤生长.
- 向CAA脂解增强了抗瘤免疫力和抗PD-1疗法的疗效.
结论:
- CAA脂解是TME中CD8+T细胞功能障碍的一个关键机制.
- 针对CAA脂解,特别是FGF21/ATGL通路,是改善癌症免疫疗法的有希望的策略.
- 通过代谢重编程恢复CD8+T细胞功效器功能,提供了一条新的治疗途径.
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