Ubiquitin E3 ligase KLHL6 brings exhausted T-cells back into action

Journal article

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.

Authors: Chen, Z; Bullock, AN; Kessler, BM

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature Singapore
• Journal: Immunity & Inflammation
• Volume: 2
• Issue: 1
• Article number: 16
• Publication date: 2026-03-05
• Acceptance date: 2026-02-19
• DOI: 10.1007/s44466-026-00032-6
• EISSN: 3059-4774
• ISSN: 3059-4774
• Language: English
• Keywords: T-cell exhaustion; Ubiquitin; E3 ligase; Kelch-like protein; CD8+ lymphocytes