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Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
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Soluble Uric Acid Drives CD8+ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation

Anyi Liu1, Fan Zuo1, Mao Li1

  • 1GI Cancer Research Institute, Tongji Hospital, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.

Cancer Research
|May 12, 2026
PubMed

Insights

Soluble uric acid (UA) drives T-cell exhaustion in colorectal cancer, hindering anti-tumor immunity. Depleting UA with febuxostat reinvigorates T cells, improving immunotherapy and chemotherapy effectiveness.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Cancer biology

Background:

  • T-cell exhaustion impairs anti-tumor immunity and immunotherapy efficacy.
  • Metabolic factors in the tumor microenvironment can trigger T-cell dysfunction.
  • Soluble uric acid (UA) is a purine metabolite often elevated in cancer patients.

Purpose of the Study:

  • To identify metabolic triggers of T-cell exhaustion in colorectal cancer (CRC).
  • To investigate the role of soluble uric acid (UA) as a metabolic checkpoint in anti-tumor immunity.
  • To explore UA depletion as a therapeutic strategy to enhance cancer immunotherapy.

Main Methods:

  • Utilized hyperuricemic mouse models of colorectal cancer.
  • Investigated the molecular mechanism of UA-induced T-cell exhaustion involving KSR1 and MAPK signaling.
  • Assessed the impact of genetic KSR1/Tim-3 disruption and pharmacological UA depletion (febuxostat) on T-cell function and tumor growth.
  • Evaluated the efficacy of febuxostat in combination with chemotherapy and adoptive T-cell therapy.

Main Results:

  • Elevated UA accelerated tumor progression in immunocompetent mice by exhausting CD8+ T cells.
  • UA directly bound KSR1, hyperactivated MEK-ERK signaling, and upregulated inhibitory receptors (PD-1, Tim-3) on CD8+ T cells.
  • Genetic disruption of the UA-KSR1-MAPK axis or pharmacological UA depletion restored T-cell effector activity and tumor control.
  • Febuxostat treatment slowed tumor growth and enhanced chemotherapy and adoptive T-cell therapy efficacy.

Conclusions:

  • Soluble uric acid acts as a metabolic immune checkpoint, driving CD8+ T-cell exhaustion and immune evasion in colorectal cancer.
  • Targeting UA metabolism, for example, via febuxostat, can reinvigorate anti-tumor T-cell immunity.
  • UA depletion presents a promising strategy to overcome immune resistance and improve cancer immunotherapy outcomes.

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