Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis, and the main objective of this study was to reveal the specific mechanism of action of TN-CAP1-mediated macrophage-fibroblast crossinulation in the progression of PDAC, and to evaluate the function and potential therapeutic value of ITGB5 and ITGB1 recombinant proteins in this process. The expression of TN-CAP1 in tumor tissues of PDAC patients was analyzed by immunohistochemistry and compared with normal pancreatic tissues. The co-culture system of macrophages and fibroblasts was constructed using in vitro cell culture model. The intercellular interactions and their effects on the proliferation, migration and invasion of tumor cells were observed by adding or knocking down ITGB5 and ITGB1 proteins. Western blot and RT-PCR were also used to detect the expression changes of related signaling pathway proteins and mRNA, which verified the effects of ITGB5 and ITGB1 recombinant proteins on tumor growth and metastasis in vivo. In vitro experiments showed that the addition of ITGB5 and ITGB1 recombinant proteins significantly enhanced the interaction between macrophages and fibroblasts, and promoted the proliferation and migration of tumor cells. Specifically, ITGB5 and ITGB1 recombinant proteins promote tumor cell aggressiveness by activating the FAK/PI3K/AKT signaling pathway.