近日，美国北卡罗来纳大学教授Jessica E. Thaxton及其团队发现了肿瘤内缺氧通过慢性激活综合应激反应转录因子ATF4促进CD8⁺ T细胞功能障碍。2025年9月25日出版的《免疫学》发表了这项成果。

该研究组研究了激活转录因子4 (ATF4)，综合应激反应（ISR）的中心节点，对肿瘤中T细胞功能障碍的贡献。患者样本中的CD8⁺肿瘤浸润淋巴细胞（TILs）表现出慢性ATF4活性，这在各种肿瘤模型中都有所反映。TME中的缺氧通过ISR激酶施加慢性ATF4活性。ATF4在CD8⁺ T细胞中的过表达诱导代谢极性、线粒体氧化应激和细胞死亡，损害抗肿瘤免疫。慢性ATF4转录活性复制了终末衰竭CD8⁺ T细胞状态，不依赖于T细胞受体（TCR）刺激。ATF4的遗传或药理学衰减降低了线粒体氧化应激，促进了CD8⁺ TIL的活力，使其对程序性细胞死亡蛋白-1（PD-1）抑制剂治疗产生反应，并赋予对复发性疾病的保护。因此，ISR聚集在CD8⁺ TIL中的慢性ATF4活性上，作为ICI反应的屏障，将ISR疗法定位为免疫治疗的候选药物。

据介绍，肿瘤微环境（TME）中的代谢应激促进T细胞功能障碍和免疫检查点抑制剂（ICI）耐药性。

附：英文原文

Title: Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4

Author: Coral del Mar Alicea Pauneto, Brian P. Riesenberg, Evelyn J. Gandy, Andrew S. Kennedy, Genevieve T. Clutton, Jessica W. Hem, Katie E. Hurst, Elizabeth G. Hunt, Jarred M. Green, Brian C. Miller, Steven P. Angus, Gary L. Johnson, Robert J. Esther, Jennifer L. Guerriero, Peng Gao, David R. Soto-Pantoja, Robert L. Ferris, Jennifer L. Modliszewski, Michael F. Coleman, H. Kay Chung, J. Justin Milner, Stergios J. Moschos, R. Luke Wiseman, Jessica E. Thaxton

Issue&Volume: 2025-09-25

Abstract: 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.

DOI: 10.1016/j.immuni.2025.09.003

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00414-5