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
TGF-β-YY1 信号通路作为胰腺癌免疫逃逸的关键驱动因素：治疗意义
英文原题：TGF-β-YY1 signaling as a key driver of immune evasion in pancreatic cancer: Therapeutic implications.
查看英文原题
TGF-β-YY1 signaling as a key driver of immune evasion in pancreatic cancer: Therapeutic implications.
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中文摘要
胰腺导管腺癌（PDAC）是一种高度致死的恶性肿瘤，其特征包括致密促纤维增生性间质、深度免疫抑制和对常规治疗耐药。患者结局不佳的原因是肿瘤内在和微环境机制共同导致化疗及免疫治疗耐药。
因此，阐明治疗失败背后的分子通路至关重要。转化生长因子β（TGF-β）是PDAC进展的核心调节因子，在疾病晚期可促进上皮—间质转化（EMT）、间质重塑、免疫排斥和免疫检查点激活。转录因子Yin Yang 1（YY1）是TGF-β驱动信号程序的重要下游整合器和放大器。YY1通过转录、表观遗传和转录后调控增强EMT、代谢适应和免疫逃逸。参与免疫逃逸的关键免疫调节因子包括PD-L1、吲哚胺2,3-双加氧酶、FOXP3和促肿瘤趋化因子。TGF-β—YY1协同信号会抑制CD8细胞毒性T细胞（CTL）和自然杀伤（NK）细胞功能，促进调节性T细胞（Treg）和髓源性抑制细胞（MDSC），并建立免疫冷、治疗耐受的肿瘤微环境。本综述探讨TGF-β—YY1相互作用调节PDAC免疫逃逸的机制基础，并讨论靶向TGF-β—YY1轴以克服免疫逃逸、改善PDAC治疗结局的新兴治疗机会。
展开英文摘要原文
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by a dense desmoplastic stroma, profound immune suppression, and resistance to conventional therapeutics. Poor patient outcomes are driven by resistance to chemotherapy and immunotherapy arising from both tumor-intrinsic and microenvironmental mechanisms. Elucidating the molecular pathways underlying therapeutic failure is therefore critical. Transforming growth factor- (TGF- ) is a central regulator of PDAC progression, promoting epithelial-mesenchymal-transition (EMT), stromal remodeling, immune exclusion, and checkpoint activation at advanced disease stages. The transcription factor Yin Yang 1 (YY1) is a critical downstream integrator and amplifier of TGF- -driven signaling programs.
YY1 reinforces EMT, metabolic adaptation, and immune evasion through transcriptional, epigenetic, and post-transcriptional regulations. Several key immune modulators of immune evasion include PD-L1, indoleamine 2,3-dioxygenase, FOXP3, and pro-tumoral chemokines. The coordinated TGF- -YY1 signaling suppresses CD8 cytotoxic T-cell (CTL) and natural killer (NK) cell functions, promotes regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and establishes an immune-cold, therapy-resistant tumor microenvironment.
This review explores the mechanistic basis of the TGF- -YY1 cross-talk regulation in the immune evasion of PDAC. It also discusses emerging therapeutic opportunities in targeting the TGF- -YY1 axis to overcome immune escape and improve treatment outcomes in PDAC.
论文信息
- 作者
- Ho MP、Jung M、Ung W、Skouradaki E、Baritaki S、Bonavida B
- 第一作者单位
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, CA 90095, USA. Electronic address: maiho123@ucla.edu.United States
- 通讯作者单位
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, CA 90095, USA. Electronic address: bbonavida@mednet.ucla.deu.United States
- 文献类型
- 综述
- 期刊
- Cytokine & growth factor reviews2026 Apr
- 原文标识
- PubMed 41558149 · DOI 10.1016/j.cytogfr.2026.01.005