Intra-tumoral hypoxia promotes CD8 T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
1/5 보강
Metabolic stress in the tumor microenvironment (TME) promotes T cell dysfunction and immune checkpoint inhibitor (ICI) resistance.
APA
Alicea Pauneto CDM, Riesenberg BP, et al. (2025). Intra-tumoral hypoxia promotes CD8 T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.. Immunity, 58(10), 2489-2504.e8. https://doi.org/10.1016/j.immuni.2025.09.003
MLA
Alicea Pauneto CDM, et al.. "Intra-tumoral hypoxia promotes CD8 T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.." Immunity, vol. 58, no. 10, 2025, pp. 2489-2504.e8.
PMID
41005293 ↗
Abstract 한글 요약
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.
🏷️ 키워드 / MeSH 📖 같은 키워드 OA만
- Humans
- Male
- Female
- Animals
- Mice
- Inbred C57BL
- Tumor Microenvironment
- Cell Hypoxia
- CD8-Positive T-Lymphocytes
- Oxidative Stress
- Cell Line
- Activating Transcription Factor 4
- Neoplasms
- Mitochondria
- Cell Death
- Programmed Cell Death 1 Receptor
- Immune Checkpoint Inhibitors
- ATF4
- T cell
- hypoxia
- immunotherapy
- integrated stress response
- metabolism
- mitochondria
… 외 1개
🏷️ 같은 키워드 · 무료전문 — 이 논문 MeSH/keyword 기반
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