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Accumulating evidence shows that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages, the predominant cells in the pancreatic cancer (PDAC) tumor microenvironment, hinder antitumor immunity. However, the role of extracellular vesicles (EVs) in such a process is poorly understood. In this study, using human bone marrow\u2013derived monocytes and PDAC tumor cells, we showed that tumor cell\u2013derived EVs (TC-EVs) induced monocyte differentiation toward M2-like, immunosuppressive, CD200R\n                    <jats:sup>+<\/jats:sup>\n                    PD-L1\n                    <jats:sup>+<\/jats:sup>\n                    HLA-DR\n                    <jats:sup>lo<\/jats:sup>\n                    macrophages that express ALOX15B, that we identify as an independent PDAC poor-prognosis biomarker using a human PDAC metacohort. We also demonstrated that TC-EVs reprogrammed human primary PDAC CAFs, causing a fibronectin network reorganization associated with changes in extracellular matrix (ECM) composition, including alterations of WNT pathway elements such as secreted frizzled related protein-1 (SFRP1) enrichment. We also revealed that monocytes cultured on SFRP1\u2013enriched ECM differentiated into M2-like, immunosuppressive macrophages. Last, we demonstrated that both directly and indirectly TC-EV\u2013 or SFRP1-enriched ECM\u2013driven differentiated macrophages hindered T cell activation and subsequent antitumor activity. Our findings highlight potentially novel dual mechanisms of TC-EV\u2013mediated crosstalk, involving ALOX15B\n                    <jats:sup>+<\/jats:sup>\n                    macrophages and SFRP1\n                    <jats:sup>+<\/jats:sup>\n                    CAFs, that simultaneously contribute to foster the immunosuppressive ecosystem of PDAC.\n                  <\/jats:p>\n                  <jats:p>This work reveals that extracellular vesicles produced by tumor cells modulate non-tumoral cells behavior to foster the establishment of an immunosppressive ecosystem, in pancreatic cancer.<\/jats:p>","DOI":"10.1172\/jci197733","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:13:17Z","timestamp":1783008797000},"source":"Crossref","is-referenced-by-count":1,"title":["Tumor cell\u2013derived extracellular vesicles foster the immunosuppressive landscape of pancreatic 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