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Mitochondrial translation drives activated CD8+ T cell dysfunction

ABSTRACT: Enhancing CD8+ T cell function is crucial for improving cancer immunotherapy. Through CRISPR screening and validation, we identified that mitochondrial translation is upregulated in activated and exhausted CD8+ T cells, leading to the accumulation of misfolded proteins that induce mitochondrial stress and contribute to T cell dysfunction. Inhibition of this over-translation using low doses of chloramphenicol (CAP) significantly enhanced the antitumor activity of activated CD8+ T cells by promoting their expansion and reducing apoptosis and exhaustion. Low-dose CAP treatment preserved oxidative phosphorylation (OXPHOS) and cytokine production while restoring mitochondrial membrane potential. Furthermore, CAP facilitated the import of mitochondrial protein precursors, shifted HSP70 pools binding toward NFATc1, and limited its nuclear translocation, thereby reducing exhaustion markers of TIM-3 and PD1. Notably, a short course of low-dose Linezolid, a commonly used antibiotic and mitochondrial translation inhibitor, improved the CD8+ T cell ratio in the peripheral blood of patients with diffuse large B cell lymphoma. These findings highlight mitochondrial translation inhibition as a promising strategy to enhance CD8+ T cell function and potentially improve the effectiveness of cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE282220 | GEO | 2025/11/18

REPOSITORIES: GEO

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