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A daily increase in the number of new cases of pancreatic ductal adenocarcinoma remains an issue of contention in cancer research. The data revealed that a global cumulated case of about 500, 000 have been reported. This has made PDAC the fourteenth most occurring tumor case in cancer research. Furthermore, PDAC is responsible for about 466,003 deaths annually, representing the seventh prevalent type of cancer mortality. PDAC has no salient symptoms in its early stages. This has exasperated several attempts to produce a perfect therapeutic agent against PDAC. Recently, immunotherapeutic research has shifted focus to the blockade of checkpoint proteins in the management and of some cancers. Investigations have centrally focused on developing therapeutic agents that could at least to a significant extent block the SIRPα-CD47 signaling cascade (a cascade which prevent phagocytosis of tumors by dendritic cells, via the deactivation of innate immunity and subsequently resulting in tumor regression) with minimal side effects. The concept on the blockade of this interaction as a possible mechanism for inhibiting the progression of PDAC is currently being debated. This review examined the structure--function activity of SIRPα-CD47 interaction while discussing in detail the mechanism of tumor resistance in PDAC. Further, this review details how the blockade of SIRPα-CD47 interaction serve as a therapeutic option in the management of PDAC., (Copyright © 2022 Elsevier Ltd. All rights reserved.)