RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
高脂饮食通过上调结直肠癌中的 CD155 促进肿瘤免疫逃逸
英文原题：High-Fat Diet Promotes Tumor Immune Evasion via CD155 Upregulation in Colorectal Cancer.
查看英文原题
High-Fat Diet Promotes Tumor Immune Evasion via CD155 Upregulation in Colorectal Cancer.
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研究概要
HFD 诱导的代谢应激通过 STAT3/CD155 轴驱动免疫逃逸。靶向该通路可能改善肥胖相关癌症中 ICB 的疗效。
研究思路结论见上方概要
背景
肥胖诱导的代谢应激会损害免疫检查点阻断（ICB）疗法的疗效，但高脂饮食（HFD）与免疫抑制之间的联系机制仍不清楚。
目的
探讨HFD诱导的代谢变化如何通过STAT3/CD155轴调节肿瘤免疫微环境。
方法
在正常或HFD条件下，使用对照、CD155过表达（CD155 OE）和STAT3敲低的CT26细胞建立了小鼠结直肠癌模型，并给予抗PD-L1治疗。通过流式细胞术、Western blotting和染色质免疫沉淀分析了肿瘤生长、免疫浸润和基因表达。
结果
HFD损害了抗PD-L1疗效并加速了肿瘤生长。机制上，HFD促进了STAT3核转位和CD155上调，减少了CD8+ T细胞浸润并增强了调节性T细胞积聚。染色质免疫沉淀证实了STAT3直接结合CD155启动子，而STAT3敲低逆转了这些效应并在HFD喂养小鼠中恢复了抗肿瘤免疫。
展开英文摘要原文
BACKGROUND
Obesity-induced metabolic stress impairs the efficacy of immune checkpoint blockade (ICB) therapy, but the mechanisms linking a high-fat diet (HFD) to immune suppression remain unclear.
OBJECTIVE
To investigate how HFD-induced metabolic changes modulate the tumor immune microenvironment through the STAT3/CD155 axis.
METHODS
Murine colorectal cancer models using control, CD155-overexpressing (CD155 OE), and STAT3 knockdown CT26 cells were established under normal or HFD conditions with anti - PD-L1 treatment. Tumor growth, immune infiltration, and gene expression were analyzed by flow cytometry, Western blotting, and chromatin immunoprecipitation.
RESULTS
HFD impaired anti - PD-L1 efficacy and accelerated tumor growth. Mechanistically, HFD promoted STAT3 nuclear translocation and CD155 upregulation, reducing CD8 + T cell infiltration and enhancing regulatory T cell accumulation. Chromatin immunoprecipitation confirmed direct STAT3 binding to the CD155 promoter, while STAT3 knockdown reversed these effects and restored antitumor immunity in HFD-fed mice.
CONCLUSION
HFD-induced metabolic stress drives immune evasion via the STAT3/CD155 axis. Targeting this pathway may improve ICB efficacy in obesity-related cancers.
论文信息
- 作者
- Liu L、Mo L、Fang J、Ling M、Lei Y、Wen Z、Liang G、Guo J
- 单位
- Department of Oncology and Hematology, He Xian Memorial Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China.China
- 期刊
- Immunological investigations2026 Feb
- 原文标识
- PubMed 41420878 · DOI 10.1080/08820139.2025.2600597