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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Zhuoyao Chen,
  • Alex N. Bullock,
  • Benedikt M. Kessler

摘要

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.