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

T-cell exhaustion in the tumor microenvironment undermines antitumor immunity and limits immunotherapy efficacy. Further defining the metabolic triggers of this dysfunctional state could provide therapeutic targets for circumventing immunosuppression. In this study, we identified soluble uric acid (UA)-an abundant purine metabolite frequently elevated in patients with cancer-as a metabolic checkpoint that drives the exhaustion of CD8+ T cells and immune evasion in colorectal cancer. In hyperuricemic mouse models, elevated UA accelerated tumor progression in immunocompetent hosts, but not in T cell-deficient ones, by functionally exhausting tumor-infiltrating CD8+ T cells. Mechanistically, UA directly bound the kinase scaffold kinase suppressor of Ras 1 (KSR1) and hyperactivated MEK-ERK signaling, leading to chronic MAPK stimulation that upregulated inhibitory receptors, including PD-1 and 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, pharmacologic 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 antitumor T-cell immunity. Targeting UA metabolism may offer a strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies. SIGNIFICANCE: A common metabolic byproduct, soluble uric acid, can act as an immune checkpoint that drives T-cell exhaustion, redefining how systemic metabolism shapes cancer progression.