<p>Reprogramming the immunosuppressive milieu in pancreatic cancer (PaCa) remains an important yet unmet therapeutic goal. Although tumor-associated macrophages (TAMs) are known to promote tumor growth and metastasis, little is known about the underlying mechanisms driving macrophage plasticity in PaCa. Herein, we show that extracellular vesicles (EVs) released by PaCa cells as well as circulating EVs in patient plasma, facilitate cellular crosstalk thereby promoting preferential skewing of recipient macrophages towards an M2-like TAM phenotype. PaCa-EV educated macrophages predominantly secrete anti-inflammatory cytokines, adapt an M2-like metabolic phenotype, have a higher expression of PD-L1, and suppress the proliferation of CD8⁺ T cells. An increased payload of miR-182-5p in PaCa-EV cargo causes a decrease in TLR4 expression in recipient macrophages and a concomitant upregulation of JAK/STAT3 pathway and elevated secretion of IL-10 and TGF-β, leading to increased PD-L1 expression. Most notably, targeted therapeutic delivery of antagomiR-182-5p in pancreatic tumor-bearing mice with varying immunogenic potential results in a significant decrease in tumor volume, increased survival, restoration of M1/M2 ratio, and an overall increase in CD8⁺ T cell activation in the TME. Taken together, we demonstrate a direct role of EVs in subverting the immune microenvironment and altering macrophage plasticity in a manner conducive to both tumor growth and proliferation. As such, a targeted delivery of microRNA inhibitors as drugs for altering macrophage plasticity may likely achieve better therapeutic response in pancreatic tumors.</p><p></p>