tRF and gastric cancer: molecular mechanism exploration and novel strategies for precision diagnosis and therapy

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality, and current diagnostic biomarkers lack sufficient sensitivity and specificity. tRNA-derived fragments (tRFs), an emerging class of non-coding RNAs, have garnered attention for their stability and regulatory roles in carcinogenesis. MAIN BODY: This review adopts a comparative perspective to evaluate the distinctive roles of tRFs in GC relative to other non-coding RNAs, particularly microRNAs (miRNAs). We summarize tRF biogenesis and classification, highlighting their unique mechanistic repertoire that encompasses both AGO2-dependent gene silencing and non-canonical protein interactions. Dysregulated tRF profiles in patient samples reveal promising diagnostic candidates (e.g., tRF-23-Q99P9P9NDD, tRF-17-18VBY9M) that demonstrate superior performance to conventional markers. However, we critically examine translational barriers including functional heterogeneity, detection challenges, and the absence of registered clinical trials. We also dissect sources of contradictory findings and propose standardized frameworks for future investigation. CONCLUSIONS: tRFs represent functionally versatile regulators with distinct advantages over miRNAs in diagnostic applications. Their clinical translation requires overcoming methodological standardization gaps and evidence thresholds through interdisciplinary efforts integrating multi-omics profiling, advanced delivery systems, and rigorous clinical validation.