Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity
- 1Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center , , ,
- 2Houston Methodist Neal Cancer Center, Houston Methodist Research Institute , , ,
- 3The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center , , ,
Abstract
CD8 ⁺ T cells play a crucial role in anti-tumor immunity; however, their functionality is compromised by exhaustion driven by chronic antigen exposure, poor tumor microenvironment, and metabolic dysfunction. Activated CD8 ⁺ T cells undergo extensive proteomic remodeling, which includes the induction of the IRE1-XBP1 signaling axis of the unfolded protein response. However, the functional consequences of sustained IRE1-XBP1 activation in exhausted CD8 ⁺ T cells remain elusive. Using a model of constitutive XBP1 activation in CD8 ⁺ T cells, we demonstrate that sustained XBP1s signaling leads to reduced homeostatic CD8 ⁺ T cell populations, impaired migratory capacity, and dampened anti-tumor immunity. Notably, pharmacological inhibition of the IRE1-XBP1 axis significantly reduces tumor burden through a dual mechanism that targets both tumor cells and the immune compartment. Our findings reveal a previously unappreciated role for XBP1s in regulating CD8 ⁺ T cell biology and highlight the IRE1-XBP1 axis as a therapeutic target in solid tumors.
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BibTeX
@article{nair2026chronic,
title = {{Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity}},
author = {Keith Alan Nair and Jessica Lee and Olivia Zaleski and Luciano Mazzoccoli and Brian Deng and Chih-Chi Andrew Hu and Stanley Ching-Cheng Huang and Andreas Wieland and Hazem E. Ghoneim and Haitao Wen and Xiaopei Huang and Bei Liu},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1940201},
url = {https://europepmc.org/article/PMC/PMC13672639},
note = {CC BY},
}
RIS
TY - JOUR
TI - Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity
AU - Keith Alan Nair
AU - Jessica Lee
AU - Olivia Zaleski
AU - Luciano Mazzoccoli
AU - Brian Deng
AU - Chih-Chi Andrew Hu
AU - Stanley Ching-Cheng Huang
AU - Andreas Wieland
AU - Hazem E. Ghoneim
AU - Haitao Wen
AU - Xiaopei Huang
AU - Bei Liu
PY - 2026
DA - 2026/10/02
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1940201
UR - https://europepmc.org/article/PMC/PMC13672639
AB - CD8 ⁺ T cells play a crucial role in anti-tumor immunity; however, their functionality is compromised by exhaustion driven by chronic antigen exposure, poor tumor microenvironment, and metabolic dysfunction. Activated CD8 ⁺ T cells undergo extensive proteomic remodeling, which includes the induction of the IRE1-XBP1 signaling axis of the unfolded protein response. However, the functional consequences of sustained IRE1-XBP1 activation in exhausted CD8 ⁺ T cells remain elusive. Using a model of constitutive XBP1 activation in CD8 ⁺ T cells, we demonstrate that sustained XBP1s signaling leads to reduced homeostatic CD8 ⁺ T cell populations, impaired migratory capacity, and dampened anti-tumor immunity. Notably, pharmacological inhibition of the IRE1-XBP1 axis significantly reduces tumor burden through a dual mechanism that targets both tumor cells and the immune compartment. Our findings reveal a previously unappreciated role for XBP1s in regulating CD8 ⁺ T cell biology and highlight the IRE1-XBP1 axis as a therapeutic target in solid tumors.
SN - 1664-3224
ER -