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
单细胞和空间转录组学揭示经典卡波西肉瘤中 mTOR 驱动的梭形细胞细胞命运和免疫逃逸
英文原题：Single-cell and spatial transcriptomics reveal mTOR-driven cellular fate of spindle cells and immune evasion in classic Kaposi's sarcoma.
查看英文原题
Single-cell and spatial transcriptomics reveal mTOR-driven cellular fate of spindle cells and immune evasion in classic Kaposi's sarcoma.
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研究概要
本研究揭示了 mTOR 驱动的 SCs 分化在 KS 发病机制中的作用，与 CKS 患者的快速临床改善相一致，这为二甲双胍在 CKS 中的治疗潜力提供了有力证据。
研究思路结论见上方概要
背景
经典Kaposi肉瘤（CKS）是一种血管生成性肿瘤，目前尚无标准化治疗方案。肿瘤中mTOR通路活性增强，通过刺激合成代谢、细胞增殖和血管生成促进肿瘤发生。本研究旨在评估mTOR抑制剂二甲双胍在CKS患者中的治疗潜力。
方法
两名连续的组织活检证实为CKS的患者接受了二甲双胍单药治疗，我们进一步利用单细胞RNA测序和空间转录组学来揭示其潜在的分子机制。
结果
在2例CKS患者中观察到快速临床缓解且无不良反应。进一步研究发现了特征性梭形细胞（SCs），其在VEGF、mTOR和缺氧信号通路中表现出高度活性，提示终末基质分化状态。此外，免疫景观的特征是CD8+ Tex和NK细胞比例高，且细胞毒性和迁移功能受到抑制。关键的是，发现SCs主要通过CXCL9-CXCR3信号轴与免疫细胞相互作用。
展开英文摘要原文
BACKGROUND
Classic Kaposi's sarcoma (CKS) is an angiogenic tumor with no standardized treatment. Increased mTOR pathway activity in tumors fuels oncogenesis by stimulating anabolic metabolism, cell proliferation, and angiogenesis. This study aimed to assess the therapeutic potential of mTOR inhibitor metformin in CKS patients.
METHODS
Two consecutive patients with biopsy-proven, CKS received metformin as monotherapy, and we further leverage single-cell RNA sequencing and spatial transcriptomics to uncover its underlying molecular mechanisms.
RESULTS
Rapid clinical response with no adverse effects was observed in 2 CKS patients. Further investigation identified characteristic spindle cells (SCs) exhibiting heightened activity in VEGF, mTOR, and hypoxia signaling pathways, suggestive of a terminal stromal differentiation state. Besides, the immune landscape was characterized by a high proportion of CD8+ Tex and NK cells displaying suppressed cytotoxicity and migration functions. Crucially, SCs were found to interact with immune cells predominantly via the CXCL9-CXCR3 signaling axis.
CONCLUSION
This study reveals the mTOR-driven differentiation of SCs in KS pathogenesis aligning with rapid clinical improvement in CKS patients, which provides compelling evidence for metformin's therapeutic potential in CKS.
论文信息
- 作者
- Su T、Yu Y、Cao X、Wang Y、Su Z、Song G、Sun L、Chen Y
- 第一作者单位
- Department of Dermatology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.China
- 通讯作者单位
- Department of Dermatology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. luyan6289@163.com.China
- 期刊
- Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico2026 Jul
- 原文标识
- PubMed 41525037 · DOI 10.1007/s12094-025-04063-0