CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
肿瘤内缺氧通过慢性激活整合应激反应转录因子 ATF4 促进 CD8(+) T 细胞功能障碍
英文原题：Intra-tumoral hypoxia promotes CD8(+) T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
查看英文原题
Intra-tumoral hypoxia promotes CD8(+) T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
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中文摘要
肿瘤微环境（TME）中的代谢应激会促进T细胞功能障碍和免疫检查点抑制剂（ICI）耐药。本研究考察了整合应激反应（ISR）的核心节点——激活转录因子4（ATF4）——对肿瘤内T细胞功能障碍的作用。患者样本中的CD8⁺TIL（肿瘤浸润淋巴细胞）表现出持续的ATF4活性，这一现象在多种肿瘤模型中也得到验证。TME中的缺氧通过ISR激酶诱发持续的ATF4活性。在CD8⁺ T细胞中过表达ATF4会导致代谢极化、线粒体氧化应激和细胞死亡，从而损害抗肿瘤免疫。持续的ATF4转录活性可在不依赖T细胞受体（TCR）刺激的情况下，重现CD8⁺ T细胞的终末耗竭状态。通过遗传或药理方式减弱ATF4，可降低线粒体氧化应激、提高CD8⁺ TIL存活率，使其能够对程序性细胞死亡蛋白1（PD-1）抑制剂治疗产生反应，并提供对疾病再度出现的保护。
因此，ISR通过使CD8⁺ TIL中的ATF4持续活化，构成ICI治疗反应的一道屏障；靶向ISR的疗法可能成为免疫治疗候选方案。
展开英文摘要原文
Metabolic stress in the tumor microenvironment (TME) promotes T cell dysfunction and immune checkpoint inhibitor (ICI) resistance.
We examined the contribution of activating transcription factor 4 (ATF4), the central node of the integrated stress response (ISR), to T cell dysfunction in tumors. CD8 + tumor-infiltrating lymphocytes (TILs) in patient samples exhibited chronic ATF4 activity, which was reflected across various tumor models. Hypoxia in the TME imposed chronic ATF4 activity via the ISR kinases. ATF4 overexpression in CD8 + T cells induced metabolic polarity, mitochondrial oxidative stress, and cell death, impairing antitumor immunity.
Chronic ATF4 transcriptional activity replicated the terminal exhaustion CD8 + T cell state independent of T cell receptor (TCR) stimulation. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted CD8 + TIL viability, enabling response to programmed cell death protein-1 (PD-1) inhibitor therapy and conferring protection from re-emergent disease.
Thus, the ISR converges on chronic ATF4 activity in CD8 + TILs as a barrier to ICI response, positioning ISR therapeutics as candidates for immunotherapy.
论文信息
- 作者
- Alicea Pauneto CDM、Riesenberg BP、Gandy EJ、Kennedy AS、Clutton GT、Hem JW、Hurst KE、Hunt EG
- 第一作者单位
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.United States
- 通讯作者单位
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: jess_thaxton@med.unc.edu.United States
- 期刊
- Immunity2025 Oct 14
- 原文标识
- PubMed 41005293 · DOI 10.1016/j.immuni.2025.09.003
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