In this study, we found that CCL5 and AREG formed a positive feedback loop between macrophages and PCCs and further sought to delineate the mechanisms by which the macrophage-CCL5-SP1-AREG loop initiates CSC development and reduces the antitumor activity of gemcitabine via the CCL5/AKT/Sp1/CD44 axis in PAAD. Here, SP1 is linked to pancreatic adenocarcinoma.