Hao Cheng, Chi Chun Wong
tRNA modifications, the most extensively and diversely modified class of RNA across all domains of life, have garnered significant and growing attention in research over the past decade. tRNA modification defects and tRNA fragmentation has been observed within a wide spectrum of cancer types, suggesting their potential as diagnostic and prognostic biomarkers. Mechanistic studies demonstrate that regulatory enzymes for tRNAs and tdRs function as oncogenes or tumor suppressors with vital roles in cancer initiation, progression, metastasis, metabolic rewiring, therapy resistance, and immune evasion, highlighting the therapeutic potential of targeting perturbed tRNA modification machinery in cancer treatment. Herein, we summarize our current understanding of the role of tRNA modifications in cancer, and outline translational and clinical implications for cancer diagnosis and treatment. Emphasis is placed on how tRNA modifications determine the fate of target tRNAs and its influence on protein expression, molecular mechanisms and cell phenotypes. Finally, we discuss the hurdles and potential solutions to translating recent knowledge of tRNA modifications into clinical practice.