2. Academic Validation
  3. The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction

The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction

  • Nature. 2026 Mar;651(8105):451-461. doi: 10.1038/s41586-025-09926-8.
Hongcheng Cheng # 1,  Yapeng Su # 2 3,  Xiaoli Pan # 1,  Yue Xu 1,  Ermei Xie 1,  Jing Du 1,  Daniel G Chen 2 4,  Xiaomeng Dai 1 5,  Raphael Gottardo 3 6,  Philip D Greenberg 7 8 9 10,  Guideng Li 11 12
Affiliations

Affiliations

  • 1 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China.
  • 2 Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 3 Herbold Computational Biology Program, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 4 Parker Institute for Cancer Immunotherapy, Seattle, USA.
  • 5 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 6 Biomedical Data Sciences, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
  • 7 Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. [email protected].
  • 8 Parker Institute for Cancer Immunotherapy, Seattle, USA. [email protected].
  • 9 Department of Immunology, University of Washington, Seattle, WA, USA. [email protected].
  • 10 Department of Medicine, University of Washington, Seattle, WA, USA. [email protected].
  • 11 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China. [email protected].
  • 12 Biomedical Basic Research Center (BBRC) of Jiangsu Province, Suzhou, China. [email protected].
  • # Contributed equally.
PMID: 41535474 DOI: 10.1038/s41586-025-09926-8
Abstract

The multifaceted dysfunction of tumour-infiltrating T cells, including exhaustion and mitochondrial dysfunction, remains a major obstacle in Cancer Immunotherapy1-6. Transcriptomic and epigenomic regulation of T cell dysfunction have been extensively studied7-9, but the role of proteostasis in regulating these obstacles remains less defined. Here we combined computational analyses of atlases of T cell exhaustion and mitochondrial fitness with performed targeted in vivo CRISPR screens, which identified the E3 ubiquitin Ligase KLHL6 as a dual-negative regulator of both T cell exhaustion and mitochondrial dysfunction. Mechanistically, KLHL6 expression promoted TOX poly-ubiquitination and subsequent proteasomal degradation, thereby attenuating the transition of progenitor exhausted T cells towards terminal exhaustion. Simultaneously, KLHL6 maintained mitochondrial fitness by constraining the excessive mitochondrial fission that occurs during chronic T cell receptor stimulation by means of post-translational regulation of the PGAM5-Drp1 axis. However, KLHL6 is naturally downregulated by T cell receptor ligation, mitigating its potentially beneficial ubiquitin Ligase activities during exposure to chronic stimulation. Enforcing KLHL6 expression in T cells markedly improved efficacy and long-term persistence against tumours and during viral infections in vivo. These findings uncover KLHL6 as a multifunctional, clinically actionable target for Cancer Immunotherapy, and highlight the potential of modulating proteostasis and ubiquitin modification to improve immunotherapy.

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