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Background: Numerous long RNAs were detected in extracellular vesicles (EVs), some of which were related with the tissue origins and immune cell types. This study examined the molecular basis of different traditional Chinese medicine syndrome diagnoses (also called syndrome differentiation) in pancreatic ductal adenocarcinoma. Methods: 128 pancreatic ductal adenocarcinoma patients with different syndrome diagnoses were retrospectively reviewed in this study. Long RNA sequencing was conducted to analyze the EV long RNA profile of plasma samples. Differentially regulated EV long RNAs were annotated and assessed for Gene Ontology pathway enrichment using DAVID. The online program xCell were used to perform the cell-type enrichment analysis. Results: An average of 15,000 annotated genes, mainly including messenger RNAs, were stably detected per sample. Different syndrome diagnoses exhibited unique EV mRNA expression profiles and therefore different enriched pathways. Gene Set Enrichment Analysis discovered transforming growth factor-ß and kirsten rat sarcoma viral oncogene homolog signaling activation as the hallmarks of cancer with Shi-Re syndrome. Cell-type enrichment analysis also revealed a varied inflammation/immune cell type distribution among patients with or without Shi-Re diagnosis. Mast cells, platelets and Tregs were significantly enriched but basophils, common lymphoid progenitors, dendritic cells, and conventional dendritic cells were decreased in patients with Shi-Re diagnosis compared with patients without Shi-Re diagnosis. Conclusion: We identified the hallmarks of cancer with different syndrome diagnoses based on plasma EV long RNA sequencing. In particular, transforming growth factor-ß and kirsten rat sarcoma viral oncogene homolog signaling activation were the hallmarks of Shi-Re syndrome, which contribute to shape an inflammatory/immune-suppressive tumor microenvironment in pancreatic ductal adenocarcinoma. [ABSTRACT FROM AUTHOR]