tRNA-Derived Small RNAs in Digestive Cancers: From Translational Regulation to Immune and Extracellular Communication.

Abstract

Transfer RNA-derived small RNAs (tsRNAs), comprising tRNA-derived fragments (tRFs) and stress-induced tRNA halves (tiRNAs), have increasingly been recognized as an important regulatory class in gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pancreatic cancer/pancreatic ductal adenocarcinoma (PC/PDAC). Research in this field has expanded from expression profiling and liquid biopsy to non-canonical translational control, metabolic adaptation, therapy resistance, immune-associated remodeling, and extracellular-vesicle (EV)-related communication. The most intensively studied and mechanistically developed area currently lies at the intracellular level. In digestive system tumors, tsRNAs can act through EIF4 displacement, AGO2/RISC-dependent silencing, direct target repression, and ribosome-associated interactions, with some of these mechanisms validated in animal models. Beyond direct regulation of gene expression, tsRNAs can also influence tumor metabolic state and thereby contribute to chemo- and radio-resistance. By contrast, studies directly examining the effects of tsRNAs on immune-cell populations remain relatively limited, and work on EV-mediated systemic propagation still largely focuses on vesicle association and biomarker value. Functional delivery and recipient-cell effects require further clarification. Among the currently summarized studies, pancreatic-derived signaling that conditions the hepatic niche represents one of the few examples approaching a cross-organ functional model. This review discusses the major functional layers of tsRNAs in digestive system tumors, beginning with the relatively mature intracellular mechanisms and then extending to emerging immune, extracellular/systemic, and host-microbe research. We also identify key unresolved problems, including nomenclature standardization, modification-aware sequencing, criteria for EV functional delivery, causal validation of microbiota-derived tsRNAs, and prospective biomarker validation against benign and inflammatory disease controls.