Ubiquitin E3 ligase KLHL6 brings exhausted T-cells back into action
Abstract
Persistent antigen stimulation drives CD8⁺ T-cell exhaustion in cancer and chronic infection, limiting immunotherapy efficacy. Two recent studies identify the ubiquitin E3 ligase Kelch-like protein KLHL6 as a key suppressor of T-cell exhaustion. KLHL6 is maintained in progenitor and memory-like T cells but lost upon chronic TCR signaling through PI3K-AKT-mediated inhibition of FOXO1. By targeting TOX and mitochondrial regulators, such as PGAM5, KLHL6 preserves T-cell function, and its restoration rescues antitumor immunity. This discovery reveals the relevance of KLHL6 mediated ubiquitylation not only in B-lymphocytes, but also in T-cells, thereby highlighting a promising new avenue for immunotherapeutic intervention.
Fields of Study & Subjects
Ubiquitin and proteasome pathways
Cancer Immunotherapy and Biomarkers
T-cell and B-cell Immunology
Publication details
- Journal / source
- Immunity & Inflammation
- Publisher
- Springer Science and Business Media LLC
- Volume
- 2
- Issue
- 1
- Pages
- 16–16
- Publication date
- 5 March 2026
- Language
- EN