<p>Background: One&nbsp; of&nbsp; the&nbsp; main&nbsp; reasons&nbsp; for&nbsp; the&nbsp; unsuccessful&nbsp; treatment&nbsp; of&nbsp; pan-creatic&nbsp; cancer&nbsp; is&nbsp; the&nbsp; intense&nbsp; desmoplastic&nbsp; pancreatic&nbsp; microenvironment.&nbsp; In&nbsp; the&nbsp; literature, the effects of mesenchymal stem cells (MSCs) and their inflammatory phenotypes on cancer cells have been a subject of controversy. Therefore, it is cru-cial to elucidate the underlying mechanisms of this interaction, especially in the context of pancreatic cancer. We aimed to investigate the effects of naive, TLR4- activated, and TLR4- inhibited phenotypes of adipose- derived MSCs (ADMSC) on pancreatic ductal cell line (Panc- 1).Methods&nbsp; and&nbsp; Materials:&nbsp; Adipose-&nbsp; derived&nbsp; MSCs&nbsp; were&nbsp; induced&nbsp; into&nbsp; a&nbsp; proin-flammatory&nbsp; phenotype&nbsp; using&nbsp; a&nbsp; 0.5&nbsp; μg/mL&nbsp; dose&nbsp; of&nbsp; TLR4&nbsp; agonist,&nbsp; while&nbsp; an&nbsp; anti-&nbsp; inflammatory&nbsp; phenotype&nbsp; was&nbsp; generated&nbsp; in&nbsp; ADMSCs&nbsp; using&nbsp; a&nbsp; 25&nbsp; μg/mL&nbsp; dose&nbsp; of&nbsp; TLR4 antagonist. We observed that the proliferation of Panc- 1 cells was inhibited when&nbsp; naive&nbsp; ADMSCs:Panc-&nbsp; 1(10:1)&nbsp; and&nbsp; proinflammatory&nbsp; ADMSCs:Panc-&nbsp; 1(10:1)&nbsp; were directly cocultured.Results: In indirect coculture, both naive and proinflammatory ADMSCs exhib-ited&nbsp; a&nbsp; significant&nbsp; 10-&nbsp; fold&nbsp; increase&nbsp; in&nbsp; their&nbsp; inhibitory&nbsp; effect&nbsp; on&nbsp; the&nbsp; proliferation&nbsp; and colony forming capacity of Panc- 1 cells, with the added benefit of inducing apoptosis.&nbsp; In&nbsp; our&nbsp; study,&nbsp; both&nbsp; naive&nbsp; and&nbsp; proinflammatory&nbsp; ADMSCs&nbsp; were&nbsp; found&nbsp; to&nbsp; regulate&nbsp; the&nbsp; expression&nbsp; of&nbsp; genes&nbsp; associated&nbsp; with&nbsp; metastasis&nbsp; (MMP2,&nbsp; KDR,&nbsp; MMP9, TIMP1, IGF2R, and COL1A1) and EMT (CDH1, VIM, ZEB1, and CLDN1) in Panc- 1 cells. Remarkably, both naive and proinflammatory ADMSCs demon-strated&nbsp; antitumor&nbsp; effects&nbsp; on&nbsp; Panc-&nbsp; 1&nbsp; cells.&nbsp; However,&nbsp; it&nbsp; was&nbsp; observed&nbsp; that&nbsp; anti-&nbsp; inflammatory&nbsp; ADMSCs&nbsp; showed&nbsp; tumor-&nbsp; promoting&nbsp; effects&nbsp; instead.&nbsp; Furthermore,&nbsp; we&nbsp; observed&nbsp; a&nbsp; reciprocal&nbsp; influence&nbsp; between&nbsp; ADMSCs&nbsp; and&nbsp; Panc-&nbsp; 1&nbsp; cells&nbsp; on&nbsp; each&nbsp; other's&nbsp; proinflammatory&nbsp; cytokine&nbsp; expressions,&nbsp; suggesting&nbsp; a&nbsp; dynamic&nbsp; interplay&nbsp; within the tumor microenvironment.Conclusions: These findings underscore the significance of both the naive state and&nbsp; different&nbsp; inflammatory&nbsp; phenotypes&nbsp; of&nbsp; MSCs&nbsp; in&nbsp; the&nbsp; microenvironment&nbsp; and&nbsp; represent a pivotal step toward the development of novel therapeutic approaches&nbsp;for&nbsp; pancreatic&nbsp; cancer.&nbsp; Understanding&nbsp; the&nbsp; intricate&nbsp; interactions&nbsp; between&nbsp; MSCs&nbsp; and&nbsp; cancer&nbsp; cells&nbsp; may&nbsp; open&nbsp; new&nbsp; avenues&nbsp; for&nbsp; targeted&nbsp; interventions&nbsp; in&nbsp; cancer&nbsp; therapy.<br></p>