{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:17:16Z","timestamp":1793395036092,"version":"4.5.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Forschung, Technologie und Raumfahrt","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies to date and characterized by a unique immunosuppressive and highly desmoplastic tumor microenvironment (TME). These features drive profound T-cell dysfunction and maintain high resistance to current immunotherapy. By recapitulating the complex 3D architecture of human PDAC, we demonstrate the key immunosuppressive mechanisms that drive T-cell dysfunction within the tumor microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>3D PDAC spheroids\u2014generated from PANC-1 cells alone or together with primary pancreatic stellate cells (PSC)\u2014were infiltrated with primary human T-cells from healthy donors, allowing controlled analysis of T-cell infiltration, activation, and checkpoint regulation. Furthermore, patient-derived spheroids (PDS) composed of primary tumor cells and cancer-associated fibroblasts were infiltrated with autologous T-cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Infiltrated T-cells exhibited a pronounced exhaustion signature, including strong upregulation of PD-1, LAG-3, and CTLA-4, closely mirroring the phenotype of tumor-infiltrating lymphocytes (TIL) isolated from PDAC patient samples. Incorporation of pancreatic stellate cells (PSC) generated a fibrotic barrier around the tumor cells that markedly restricted T-cell infiltration, modeling the desmoplastic TME characteristic of PDAC. From a mechanistic perspective, stromal CXCL12\u2013CXCR4 enhanced T-cell exclusion: pharmacological CXCR4 blockade with AMD3100 significantly enhanced T-cell infiltration into PSC-containing spheroids. Furthermore, treatment with the anti-PD-1 monoclonal antibody pembrolizumab partially restored the effector cell function of T-cells within the 3D system. These results demonstrate that this minimalistic platform is capable of capturing complex, cytokine- and stroma-driven immunomodulation typically observed only in advanced organoid or\n                      <jats:italic>in vivo<\/jats:italic>\n                      systems. Crucially, key immunological features\u2014including T-cell exhaustion, stromal exclusion, and therapeutic responsiveness\u2014were fully reproduced in PDS. PDS reproduced patient-specific T-cell suppression patterns and therapeutic responses, underscoring the translational relevance of the platform.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, our findings identify critical determinants of T-cell dysfunction in PDAC and introduce a versatile, animal-free 3D model that powerfully captures hallmark immune-evasion mechanisms in PDAC. This system provides a scalable and mechanistically faithful tool for dissecting TME-driven immune suppression and for accelerating the functional evaluation of immunotherapeutic strategies, including patient-tailored approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1844781","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:35:04Z","timestamp":1784612104000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting stroma-mediated T-cell exclusion and functional exhaustion in pancreatic ductal adenocarcinoma through CXCR4 and PD-1 blockade"],"prefix":"10.3389","volume":"17","author":[{"given":"Alina","family":"Deipenbrock","sequence":"first","affiliation":[{"name":"Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf, Institute of Pharmaceutical Biology and Biotechnology","place":["D\u00fcsseldorf, North Rhine-Westphalia, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Hofer","sequence":"additional","affiliation":[{"name":"Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf, Institute of Pharmaceutical Biology and Biotechnology","place":["D\u00fcsseldorf, North Rhine-Westphalia, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben E.","family":"Wilmes","sequence":"additional","affiliation":[{"name":"Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf, Institute of Pharmaceutical Biology and Biotechnology","place":["D\u00fcsseldorf, North Rhine-Westphalia, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timur","family":"Cetin","sequence":"additional","affiliation":[{"name":"Carl von Ossietzky Universit\u00e4t Oldenburg, University Hospital for Visceral Surgery, Pius-Hospital Oldenburg","place":["Oldenburg, Lower Saxony, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Esposito","sequence":"additional","affiliation":[{"name":"University Hospital D\u00fcsseldorf, Institute of Pathology","place":["D\u00fcsseldorf, North Rhine-Westphalia, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Weyhe","sequence":"additional","affiliation":[{"name":"Carl von Ossietzky Universit\u00e4t Oldenburg, University Hospital for Visceral Surgery, Pius-Hospital Oldenburg","place":["Oldenburg, Lower Saxony, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Stegmaier","sequence":"additional","affiliation":[{"name":"Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf, Center for Digital Medicine, Group Machine Learning for Medical Data","place":["D\u00fcsseldorf, North Rhine-Westphalia, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole 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