Deoxycytidine kinase inhibition: Rewiring tumor nucleotide metabolism for therapeutic gain

Deoxycytidine kinase (dCK) is the rate-limiting enzyme of the deoxyribonucleoside salvage pathway, phosphorylating deoxyadenosine, deoxycytidine, and deoxyguanosine to sustain intracellular deoxyribonucleoside triphosphate (dNTP) pools. Replication stress and DNA damage enhance dCK activity, creating tumor dependence on salvage-mediated dNTP supply for DNA repair and survival. Genetic contexts such as BRCA2 loss and mutant p53 further heighten this vulnerability. This review synthesizes mechanistic evidence linking dCK to stress-adaptive nucleotide metabolism, summarizes progress in small-molecule dCK inhibitor development, and highlights dCK inhibitor TRE-515 as the first clinically tested agent, alongside plasma nucleoside profiling and PET imaging as translational pharmacodynamic biomarkers.