Emerging roles of non-coding RNAs in the tumor microenvironment of pancreatic cancer: Focusing on current challenges and future directions.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its highly complex and immunosuppressive tumor microenvironment (TME). In recent years, non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, circular RNAs, and other regulatory RNA species, have emerged as critical mediators of cellular communication and functional remodeling within the PDAC TME. These molecules regulate tumor-stroma interactions, immune evasion, angiogenesis, metabolic reprogramming, and therapeutic resistance, thereby shaping disease progression. However, the pleiotropy of ncRNAs, together with the profound cellular and molecular heterogeneity of the PDAC TME, continues to hinder mechanistic interpretation and clinical translation. In this review, we summarize current knowledge on the multifaceted roles of ncRNAs across major cellular compartments of the TME, highlight key barriers that limit their diagnostic and therapeutic potential, and discuss emerging strategies, including single-cell and spatial transcriptomics, organoid and PDX models, and nanomedicine-based delivery systems, that may accelerate the development of ncRNA-guided precision medicine in PDAC. A deeper understanding of ncRNA-mediated TME regulation is essential for improving prognostic assessment and designing more effective therapeutic interventions for this devastating disease.