Pancreatic cancer remains one of the most lethal malignancies, largely due to late diagnosis, marked tumor heterogeneity, and profound resistance to therapy. Beyond recurrent alterations in protein-coding genes, growing evidence identifies non-coding RNAs (ncRNAs) as key regulators of pancreatic cancer biology and promising tools for clinical translation, particularly in pancreatic ductal adenocarcinoma (PDAC). ncRNAs, including microRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and emerging short RNA species such as small nucleolar RNAs, PIWI-interacting RNAs, and tRNA-derived fragments, modulate gene expression through transcriptional, post-transcriptional, and epigenetic mechanisms. This review synthesizes current knowledge on ncRNA dysregulation across pancreatic cancer entities and highlights their roles in tumor initiation, proliferation, epithelial-mesenchymal transition, invasion, metastatic dissemination, immune evasion, and resistance to chemotherapy and targeted therapies. Beyond tumor-intrinsic effects, ncRNAs actively shape the tumor microenvironment by regulating stromal activation, fibrosis, metabolic adaptation, hypoxia responses, and intercellular communication via extracellular vesicles. Importantly, ncRNAs are emerging as minimally invasive biomarkers for early detection, risk stratification, prognosis, and treatment monitoring. Circulating and extracellular vesicle-associated ncRNAs show particular promise for improving diagnostic accuracy and guiding therapeutic decision-making. In parallel, therapeutic strategies targeting ncRNA pathways, including miRNA mimics, antisense oligonucleotides, RNA interference technologies, and advanced delivery systems, are advancing toward clinical application. Key barriers to clinical implementation include assay standardization, delivery specificity, off-target effects, and the need for large-scale prospective validation. Together, ncRNAs represent central regulators of pancreatic cancer pathobiology and hold significant potential to enable biomarker-driven patient stratification and RNA-based precision therapies. • ncRNAs drive PDAC progression, metastasis and therapy resistance. • Circulating and EV-associated ncRNAs enable non-invasive detection. • ncRNAs regulate stroma, immunity, metabolism and hypoxia responses. • RNA-targeted therapies include antisense, mimics and RNA interference. • Targeting ncRNAs may overcome chemoresistance and immune evasion.
Carretero-Fernández et al. (Mon,) studied this question.