Liquid Biopsy Frontiers in Pancreatic Cancer: Insights from Circulating Cell-Free Nucleic Acids

Pancreatic cancer (PC) remains one of the most aggressive and lethal malignancies worldwide, largely due to late diagnosis, aggressive biology, limited therapeutic options and responsiveness. Conventional diagnostic and monitoring strategies, including imaging and serum biomarkers such as CA 19-9, provide limited sensitivity for early detection and suboptimal accuracy for the dynamic assessment of treatment response and disease evolution. These limitations highlight the urgent need for innovative, minimally invasive approaches capable of improving patient stratification and guiding personalized management. In this context, liquid biopsy has emerged as a promising, minimally invasive approach able to capture tumor-derived molecular information through the analysis of circulating cell-free nucleic acids, including circulating cell-free DNA (cfDNA) and circulating cell-free RNA (cfRNA). Released into the bloodstream by tumor cells, these analytes offer a real-time and comprehensive snapshot of tumor biology, capturing genetic, epigenetic, and transcriptional alterations through a simple blood draw. Liquid biopsy-based analyses hold significant potential for early detection, prognostic assessment, therapeutic decision-making, monitoring of minimal residual disease, and identification of resistance mechanisms. This review discusses the current state of research on circulating cell-free nucleic acids in PC, highlighting their biological basis, methodological approaches, clinical potential, and the challenges limiting their widespread implementation. By underscoring their translational relevance, we aim to outline how integrated liquid biopsy strategies, alongside the need for standardization and cross-study harmonization, may contribute to a more precise and dynamic approach to PC management.