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.