Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor-associated macrophages (TAMs) have been implicated in the pathogenesis of immune suppression of the PDA TME; however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that, in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of the PDA TAMs was significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, was significantly decreased in the PDA TAMs. We demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA TAMs promoted phagocytosis through the regulation of the signaling cascades involved in the process. Using an ex vivo culture model of primary human PDA, we showed that VentX-modulated TAMs transformed the PDA TME from a protumor milieu to an antitumor microenvironment by rectifying differentiation, proliferation, and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated TAMs exerted strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.