Pancreatic cancer is characterized by high malignancy, rapid progression, early metastasis, chemotherapy resistance, and no specific targeted drugs due to its complex tumor microenvironment (TME). Pancreatic stellate cells (PSCs) are inert lipid storage cells of the pancreas and an important part of the TME. Targeting tumor-stromal crosstalk in the TME has become a promising therapeutic strategy against pancreatic cancer progression and metastasis. Therefore, the authors address the interaction of PSCs in the pancreatic cancer TME and the potential treatment application of targeted activation of PSCs, to provide new targets and new ideas for the treatment of pancreatic cancer.