Simple SummaryPancreatic cancer ranks as the fourth leading cause of cancer-related death in the United States. In fact, it is estimated that there will be 64,050 new cases and 50,550 deaths in 2023 in the US alone. Pancreatic ductal adenocarcinoma accounts for the vast majority of pancreatic cancer cases, and it has been widely recognized as one of the most devastating malignancies. The majority of patients are diagnosed at late stages when metastasis has occurred, leading to the 5-year survival rate being below 10%, which is the lowest among all cancer types. The causes of death are largely attributed to scanty screening diagnostic tools, abrupt metastasis, and prevalent chemoresistance. Molecular studies have elucidated that the stiff fibroblastic stroma shields from the penetration of therapeutic agents and establishes a hypoxic niche. A growing body of evidence identifies that tumor-associated macrophages play pivotal roles contributing to mortality by strengthening the fibroblastic stroma, promoting malignant cell proliferation, augmenting angiogenesis, metastasis, acquiring pleiotropic pancreatic cancer stem-like cells, supporting chemoresistance, and harnessing an immune-suppressive microenvironment that subsequently dampens chemo- and immunotherapies. This review will summarize research findings revealing various mechanisms employed to polarize macrophages to tumor-supporting subtypes which subsequently unleash the plethora of neoplastic characteristics. In addition, it will ignite potential targets aiming to correct the aberrant carcinogenic regulators through therapeutic approaches.AbstractMounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.