Abstract 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.
Liu et al. (Tue,) studied this question.