Tumor cell-derived extracellular vesicles foster the immunosuppressive landscape of pancreatic cancer

Zainab Hussain; Claudio Montenegro; Christopher Rovera; Djamila Belghoula; Sarah simha Tubiana; Pascal Finetti; Eugenie Lohmann; Magda Rodrigues; Thomas Bertran; Ghislain Bidaut; Daniel Isnardon; Sophie Vasseur; Francois Bertucci; Stephane Audebert; Luc Camoin; Moacyr Rego; Richard Tomasini

doi:10.1172/JCI197733

¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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¹Institute Paoli-Calmettes, Cancer Research Center of Marseille, Marseille, France

²Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil

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J Clin Invest. https://doi.org/10.1172/JCI197733.
Copyright © 2026, Hussain et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published July 2, 2026 - Version history

Pancreatic cancer remains a devastating disease with limited therapeutic options. Accumulating evidence has shown that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), the predominant cells in the pancreatic cancer (PDAC) tumor microenvironment (TME), hinder anti-tumor immunity. However, the role of extracellular vesicles (EVs) in such process is poorly understood. In this study, using human bone-marrow-derived monocytes and PDAC tumor cells, we show that tumor cell-derived EVs (TC-EVs) induced monocyte differentiation towards M2-like immunosuppressive CD200R⁺/PD-L1⁺/HLA-DR^- macrophages that express ALOX15b, that we identify as an independent PDAC poor-prognosis biomarker using a human pancreatic cancer metacohort. We also demonstrate that TC-EVs reprogram human primary PDAC CAFs, causing a fibronectin network reorganization associated with changes in extracellular matrix (ECM) composition, including alterations of the Wnt pathway elements such as SFRP1 enrichment. We further reveal that monocytes cultured on rSFRP1-enriched ECM differentiate also into M2-like immunosuppressive macrophages. Lastly, we demonstrate that both directly and indirectly TC-EVs, or rSFRP1-enriched ECM, driven differentiated macrophages hindered T-cell activation and subsequent anti-tumor activity. Our findings highlight novel, dual mechanisms of TC-EVs-mediated crosstalk, involving Alox15b⁺-Macrophages and SFRP1⁺-CAFs, that simultaneously contribute to foster the immunosuppressive ecosystem of pancreatic cancer.

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Tumor cell-derived extracellular vesicles foster the immunosuppressive landscape of pancreatic cancer

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