Targeting tRNA-Arg-TCT-4-1 suppresses cancer cell growth and tumorigenesis

tRNAs play a critical role in protein synthesis, influencing mRNA translation dynamics to shape proteomes. Emerging evidence links dysregulated tRNA activity to cancer progression, with tRNA-Arg-TCT identified as an oncogenic driver when ectopically overexpressed in non-malignant cells. The requirement of endogenous tRNA-Arg-TCT in cancer biology, however, remains untested. Moreover, considering that the tRNA-Arg-TCT family comprises six genes in humans, the importance of an individual tRNA isodecoder in cancer remains unknown. Here, we find elevated levels of tRNA-Arg-TCT-4-1 isodecoder are associated with poor patient prognosis across multiple cancer types. We demonstrate that, using different antisense RNA strategies, specific inhibition of tRNA-Arg-TCT-4-1 suppresses the growth of glioblastoma (GBM) and liposarcoma (LPS) cancer cells. Mechanistically, we find that tRNA-Arg-TCT-4-1 inhibition leads to a codon-biased remodeling of mRNA translation and the proteome, preferentially suppressing expression of growth-promoting genes and pathways encoded by mRNAs enriched in arginine AGA codons. Strikingly, intratumoral delivery of an antisense oligonucleotide (ASO) targeting tRNA-Arg-TCT-4-1 suppresses tumor growth and extends survival in mouse xenograft experiments performed using either a human LPS cell line or a patient-derived soft tissue sarcoma model. This study provides a foundation for targeting tRNA dysregulation as a novel therapeutic approach for cancer.