Research Article: Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8 + T cell anti-tumor immunity
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.
Introduction:
CD8 + T cells are central effectors of tumor control and anti-tumor immunity. However, strategies to improve their functionality remain an active area of investigation ( 1 – 6 ). Upon activation, CD8 + T cells undergo extensive proteomic remodeling, resulting in a three- to fourfold increase in total cellular protein content ( 7 ). This heightened biosynthetic demand necessitates tightly regulated protein quality control mechanisms to maintain protein homeostasis, including activation of the unfolded protein…
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