tRNA-derived small RNAs in tumor microenvironment remodeling: From mechanistic insights to therapeutic perspectives

Transfer RNA-derived small RNAs (tsRNAs) represent an emerging class of non-coding RNAs involved in gene expression and cellular homeostasis. Growing evidence suggests that tsRNAs contribute to tumor initiation and progression, in part by reshaping the tumor microenvironment (TME). This review systematically summarizes the biogenesis and molecular mechanisms of tsRNAs and discusses how they regulate key TME-associated processes, including immune cell function, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated intercellular communication. We further examine their clinical relevance, focusing on circulating biomarkers, therapeutic targeting and delivery strategies, as well as current limitations for translation. In the tumor microenvironment, tRNA-derived small RNAs regulate multiple interconnected processes, including immunosuppression, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated cell-cell communication, thereby contributing to tumor progression.