Soluble Uric Acid Drives CD8⁺ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation

T-cell exhaustion in the tumor microenvironment undermines anti-tumor immunity and limits immunotherapy efficacy. Further defining the metabolic triggers of this dysfunctional state could provide therapeutic targets for circumventing immunosuppression. Here we identified soluble uric acid (UA)-an abundant purine metabolite frequently elevated in cancer patients-as a metabolic checkpoint that drives exhaustion of CD8⁺ T cells and immune evasion in colorectal cancer (CRC). In hyperuricemic mouse models, elevated UA accelerated tumor progression in immunocompetent hosts, but not T-cell-deficient ones, by functionally exhausting tumor-infiltrating CD8⁺ T cells. Mechanistically, UA directly bound the kinase scaffold KSR1 and hyperactivated MEK-ERK signaling, leading to chronic MAPK stimulation that upregulated inhibitory receptors, including PD-1, Tim-3, on CD8⁺ T cells and blunted their cytotoxic function. Genetic disruption of this UA-KSR1-MAPK axis via Tim-3 knockout or Ksr1 knockdown restored T-cell effector activity and tumor control. Notably, pharmacological UA depletion with the clinical xanthine oxidase inhibitor febuxostat reinvigorated CD8⁺ T cells, slowing tumor growth and markedly enhancing the efficacy of both chemotherapy and adoptive T cell therapy in vivo. These findings establish soluble UA as a metabolic immune checkpoint that subverts anti-tumor T-cell immunity. Targeting UA metabolism may offer a strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies.