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

Coral Del Mar Alicea Pauneto¹, Brian P Riesenberg², Evelyn J Gandy², Andrew S Kennedy³, Genevieve T Clutton², Jessica W Hem⁴, Katie E Hurst², Elizabeth G Hunt³, Jarred M Green⁴, Brian C Miller⁵, Steven P Angus¹, Gary L Johnson¹, Robert J Esther⁶, Jennifer L Guerriero⁷, Peng Gao⁸, David R Soto-Pantoja⁹, Robert L Ferris¹⁰, Jennifer L Modliszewski², Michael F Coleman¹¹, H Kay Chung³, J Justin Milner⁴, Stergios J Moschos⁵, R Luke Wiseman¹², Jessica E Thaxton¹³

Affiliations

¹ 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.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ 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.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Orthopedics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA; Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Medicine, Metabolomics Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁹ Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, USA.
¹³ 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.

PMID: 41005293
PMCID: PMC12666857 (available on 2026-09-25)
DOI: 10.1016/j.immuni.2025.09.003

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

Coral Del Mar Alicea Pauneto et al. Immunity. 2025.

. 2025 Oct 14;58(10):2489-2504.e8.

doi: 10.1016/j.immuni.2025.09.003. Epub 2025 Sep 25.

Authors

Affiliations

¹ 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.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ 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.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Orthopedics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA; Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Medicine, Metabolomics Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁹ Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, USA.
¹³ 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.

PMID: 41005293
PMCID: PMC12666857 (available on 2026-09-25)
DOI: 10.1016/j.immuni.2025.09.003

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.

Keywords: ATF4; T cell; hypoxia; immunotherapy; integrated stress response; metabolism; mitochondria; tumor microenvironment.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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

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

Authors

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Abstract

Conflict of interest statement

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