The tRNA Landscape in Cancer: From Pathogenesis to Therapeutic Interventions

Abstract

Transfer RNA (tRNA) acts not only as an indispensable adaptor in protein synthesis but also as a key contributor to tumorigenesis when its regulation is disrupted. This review systematically summarizes aberrant tRNA-related mechanisms in cancer, including altered tRNA expression profiles, abnormal post-transcriptional modifications, dysregulated aminoacylation, production of tRNA-derived small RNAs (tdRs), and defects in tRNA trafficking and translational fidelity. Notably, the metabolically abnormal tumor microenvironment actively shapes tRNA reprogramming to facilitate adaptive survival, while dysregulated tRNA elements, such as specific modifications and tdRs, further drive cancer stem cell properties and therapeutic resistance. Collectively, these alterations reprogram the oncoproteome and signaling networks, thereby promoting tumor cell proliferation, metastasis, immune evasion, and drug resistance. Targeting these mechanisms represents a promising strategy for developing novel cancer therapies. Potential approaches include the use of suppressor tRNAs to restore tumor suppressor gene function, the employment of tdRs to modulate oncogenic signaling pathways, or direct inhibition of enzymes involved in tRNA biogenesis. These strategies aim to remodel the dysfunctional tRNA network in cancer and offer new avenues for innovative treatments.

1. Introduction

tRNA serves as a core molecular adaptor that decodes the genetic code and ensures accurate translation of mRNA into functional proteins. Although tRNA has been long viewed as a constitutive and passive housekeeping molecule, accumulating evidence demonstrates that it functions as a dynamic regulator of gene expression beyond its canonical role in translation [1]. Tight control of tRNA biology, including transcription, nuclear export, nucleotide modification, aminoacylation, and turnover, is essential for cellular homeostasis. Disruption of any of these processes can reshape the cellular proteome and contribute to disease.

The human genome is predicted to encode 417 high-confidence tRNA genes, as identified using the tRNAscan-SE tool [2], many of which are present in multiple copies. Changes in the abundance or activity of specific tRNAs are strongly linked to pathological conditions, particularly cancer. Tumor cells actively exploit tRNA regulatory networks to sustain rapid growth, invasion, and survival. To satisfy elevated translational demands, cancer cells undergo both global and selective alterations in tRNA expression [3–5]. Abnormal epitranscriptomic tRNA modifications preferentially enhance the translation of codon-biased oncogenic mRNAs [6]. Dysregulated aminoacyl-tRNA synthetases (ARSs) increase tRNA charging efficiency [7] and may also acquire non-canonical oncogenic functions [8]. Errors in tRNA-mediated decoding promote tumor progression by increasing translational misreading [9]. In parallel, selective nuclear export of specific tRNA isoacceptors facilitates efficient translation of pro-tumorigenic transcripts [10]. Moreover, the production of functional tdRs enables post-transcriptional gene regulation in a manner similar to microRNAs [11]. Critically, such tRNA reprogramming is exacerbated under tumor microenvironmental stress, such as metabolic and oxidative stress, driving adaptive survival, while dysregulation of specific tRNAs and tdRs is instrumental in maintaining cancer stemness and fostering therapy resistance. Collectively, these mechanisms drive an extensive yet controlled rewiring of the cancer proteome, enabling tumor cells to adapt, evade apoptosis, shape an immunosuppressive milieu, and promote metastasis.