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
BCAP31 通过氧化磷酸化依赖性巨噬细胞免疫抑制促进结直肠癌转移：一项单细胞转录组研究
英文原题：BCAP31 promotes colorectal cancer metastasis via oxidative phosphorylation-dependent macrophage immunosuppression: A single-cell transcriptomic study.
查看英文原题
BCAP31 promotes colorectal cancer metastasis via oxidative phosphorylation-dependent macrophage immunosuppression: A single-cell transcriptomic study.
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中文摘要
结直肠癌（CRC）是一种高度异质性的恶性肿瘤，其复杂的肿瘤微环境（TME）导致免疫治疗耐药。通过对CRC组织进行单细胞RNA测序（scRNA-seq）分析，我们鉴定出巨噬细胞是主要的免疫亚群（占TME的16 %），其通过HLA-CD8A和COL1A1/2-CD44信号通路与NK细胞和成纤维细胞相互作用，促进免疫抑制。
我们开发了一个10基因巨噬细胞相关预后特征（包括BCAP31、PKM和IFNGR1），可有效将患者分为高风险组和低风险组，其中高风险病例表现出M0/M2巨噬细胞富集、Treg浸润以及对免疫治疗耐药（TIDE评分，p = 2.5e-06）。功能验证揭示，BCAP31作为一个关键风险基因，促进CRC细胞侵袭和迁移，而IFNGR1则表现出保护作用，并得到孟德尔随机化的支持（OR = 0.72）。
我们的发现强调了巨噬细胞驱动的免疫失调在CRC进展中的关键作用，并提出BCAP31作为潜在治疗靶点，为TME中线粒体-免疫串扰提供了新的见解。
展开英文摘要原文
Colorectal cancer (CRC) is a highly heterogeneous malignancy with a complex tumor microenvironment (TME) that contributes to immunotherapy resistance. Through single-cell RNA sequencing (scRNA-seq) analysis of CRC tissues, we identified macrophages as a dominant immune subset (16 % of TME) that interacts with NK cells and fibroblasts via HLA-CD8A and COL1A1/2-CD44 signaling, promoting immunosuppression.
We developed a 10-gene macrophage-related prognostic signature (including BCAP31, PKM, and IFNGR1) that effectively stratified patients into high- and low-risk groups, with high-risk cases exhibiting enriched M0/M2 macrophages, Treg infiltration, and resistance to immunotherapy (TIDE score, p = 2. 5e-06). Functional validation revealed that BCAP31, a key risk gene, promotes CRC cell invasion and migration, while IFNGR1 demonstrated a protective role supported by Mendelian randomization (OR = 0. 72).
Our findings highlight the critical role of macrophage-driven immune dysregulation in CRC progression and propose BCAP31 as a potential therapeutic target, offering new insights into mitochondrial-immune crosstalk in the TME.
论文信息
- 作者
- He Y、Song H、Lv H、Zheng X、Chen X
- 第一作者单位
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China; Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China; Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China.China
- 通讯作者单位
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China; Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China; Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China. Electronic address: chenxb01972@163.com.China
- 期刊
- Free radical biology & medicine2025 Nov
- 原文标识
- PubMed 40769312 · DOI 10.1016/j.freeradbiomed.2025.08.002