IL1RA(+) Myeloid-derived Suppressor Cells Activate Epithelial-mesenchymal Transition to Facilitate Lymphatic and Hepatic Metastasis in Pancreatic Ductal Carcinoma.

BACKGROUND AND AIMS: Hepatic metastasis (HM) and lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC) are associated with worse overall survival, largely due to the immunosuppressive microenvironment. However, the key immunosuppressive cells within this microenvironment remain inadequately defined. This study aimed to identify the cells contributing to HM and lymph node metastasis in PDAC and to investigate their regulatory mechanisms. METHODS: Single-cell RNA sequencing was used to profile the tumor microenvironment in HM, lymph node-negative, and lymph node-positive (LNP) PDAC tissues. Bioinformatic analyses revealed subtypes of immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunofluorescence and flow cytometry were performed to detect the distribution and proportion of interleukin-1 receptor antagonist (IL1RA(+)) MDSCs. The immunosuppressive and pro-tumorigenic functions of IL1RA(+) MDSCs were analyzed using enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and Transwell assays. Patient-derived xenograft mouse models were employed to validate the role of IL1RA(+) MDSCs in vivo. RESULTS: Polymorphonuclear-MDSCs were found to be recruited to metastatic PDAC tissues. Among these, IL1RA(+) MDSCs were enriched in HM/LNP tissues and correlated with poorer prognosis. IL1RA(+) MDSCs promoted M2 macrophage polarization and suppressed the activity of natural killer cells and cytotoxic T cells. Furthermore, IL1RA(+) MDSCs accelerated PDAC migration and progression by upregulating epithelial-mesenchymal transition-related proteins in both in vitro and in vivo models. CONCLUSIONS: IL1RA(+) MDSCs represent a key immunosuppressive and pro-tumorigenic subtype in HM/LNP PDAC, providing a solid theoretical basis for prognostic prediction and the development of immunotherapeutic strategies targeting these cells in HM/LNP PDAC.