NUDT enzymes shape cancer metabolism genome maintenance and therapeutic response

NUDT enzymes are a heterogeneous group of Nudix hydrolases that connect nucleotide and metabolite turnover with genome maintenance, RNA regulation, and therapeutic response in cancer. Although these proteins share a conserved metal-dependent catalytic motif, their biological effects differ widely because they act on distinct substrates, including oxidized nucleotides, ADP-ribose derivatives, CoA species, nucleotide sugars, RNA caps, and polyadenylation-associated RNA-processing machinery. This review evaluates the cancer relevance of representative NUDT family members with an emphasis on evidence strength. MTH1/NUDT1, NUDT5, NUDT7, NUDT13, NUDT18, DCP2, NUDT21, and NUDT22 illustrate how NUDT biology intersects with oxidative stress, replication stress, metabolic rewiring, DNA repair, RNA stability, alternative polyadenylation, and treatment resistance. Among these proteins, NUDT15 currently has the clearest clinical utility because germline variants reproducibly predict thiopurine intolerance and guide dose adjustment in acute lymphoblastic leukemia and other thiopurine-treated conditions. By contrast, inhibitor-based strategies directed at MTH1/NUDT1, NUDT5, NUDT18, NUDT21, and NUDT22 remain largely preclinical and require stronger biomarker stratification, tumor-context validation, and normal-tissue toxicity assessment. We further highlight the context-dependent behavior of NUDT proteins, as the same member may support or restrain tumor progression depending on lineage, genetic background, metabolic state, and treatment exposure. A clinically useful framework for NUDT-directed oncology will therefore require not only target discovery, but also substrate-level mechanistic definition, evidence grading, and therapeutic-window evaluation.