SDC-1 deficiency enhances the pancreatic cancer response to PD-1 antibody by reprogramming tumor microenvironment

Immunotherapy with PD-1 antibody for pancreatic cancer faces significant challenges due to the intricate tumor microenvironment. Syndecan-1 ( SDC-1 ), a type I transmembrane heparan sulfate proteoglycan, plays a crucial role in paracrine and epithelial-stromal interactions. However, its functional and clinical significance in the development and immunotherapy of pancreatic cancer remains unclear. Here, we report that targeting SDC-1 is a potential strategy to enhance therapeutic efficacy of PD-1 on pancreatic cancer by regulating tumor microenvironment. Our analysis reveals that SDC-1 is upregulated in pancreatic cancer tissues compared to normal pancreatic tissues. High SDC-1 expression correlates negatively with patient prognosis, as demonstrated through publicly available databases and tissue microarrays from pancreatic cancer patients. Overexpression of SDC-1 in PANC-1 cells promoted proliferation, migration, and invasion of pancreatic cancer cells, while SDC-1 knockdown significantly reduced these activities. In vivo, SDC-1 knockdown inhibited tumor growth and prolonged survival in mice with subcutaneous pancreatic cancer tumors. Crucially, SDC-1 ablation significantly enhanced the response of pancreatic cancer to PD-1 antibody treatment by reducing collagen deposition and cancer-associated fibroblast (CAF) levels in the stroma, while promoting increased infiltration of CD4 + and CD8 + T cells. Taken together, our findings suggest that SDC-1 is a critical oncogene in pancreatic cancer. Its deficiency leads to significant sensitization to immunotherapy by reprogramming the tumor microenvironment, offering a promising strategy to improve PD-1 antibody efficacy in pancreatic cancer treatment.