Data Sheet 1_Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity.pdf

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.