{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:06:01Z","timestamp":1779883561896,"version":"3.53.1"},"reference-count":165,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and largely refractory to immune checkpoint inhibition because limited antigen-specific priming, myeloid suppression, dense desmoplasia, and abnormal vasculature enforce immune exclusion. CD40 links CD4+ T-cell help through CD40L\/CD154 to antigen-presenting-cell (APC) licensing and CD8+ T-cell priming, making CD40 agonism a rational strategy to stimulate antitumor immunity in PDAC. CD40 is expressed on APCs and has also been reported on subsets of PDAC tumor cells, cancer-associated fibroblasts, and endothelial cells, indicating that CD40 agonists may affect immune activation, stromal\/vascular remodeling, and context-dependent tumor-cell-intrinsic signaling. TRAF-dependent CD40 signaling activates canonical and non-canonical NF-kB, MAPK, and PI3K\/AKT pathways, promoting APC maturation, IL-12-associated Th1 programming, macrophage repolarization, and matrix remodeling; tumor-intrinsic effects remain more variable, ranging from apoptotic to pro-survival programs. Clinically, CD40 agonists have shown pharmacodynamic immune engagement and manageable toxicity, mainly in combinations with chemotherapy, checkpoint inhibitors, and vaccine platforms, but efficacy remains inconsistent, and randomized validation is incomplete. Baseline CD40 expression has not reliably predicted benefit. Future development should prioritize spatially resolved tumor-immune profiling, longitudinal pharmacodynamic biomarkers, optimized sequencing, and agent-specific dosing strategies. This review integrates CD40 expression, signaling, and clinical evidence in PDAC to support more rational, biomarker-guided development of CD40-directed immunotherapy.<\/jats:p>","DOI":"10.3390\/cancers18111743","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:03:27Z","timestamp":1779879807000},"page":"1743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD40 Agonism in Pancreatic Ductal Adenocarcinoma: Expression, Biology, and Therapeutic Targeting"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5029-1519","authenticated-orcid":false,"given":"Songul","family":"Kucukcelebi","sequence":"first","affiliation":[{"name":"Solid Tumor Immunology Research Rotterdam (STIRR) Group, Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0192-5354","authenticated-orcid":false,"given":"Aniek E. van","family":"Diepen","sequence":"additional","affiliation":[{"name":"Solid Tumor Immunology Research Rotterdam (STIRR) Group, Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Internal Medicine, Division of Medical Oncology, GROW Research Institute for Oncology & Reproduction, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith de","family":"Vos-Geelen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Oncology, GROW Research Institute for Oncology & Reproduction, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9511-2157","authenticated-orcid":false,"given":"Casper H. J.","family":"van Eijck","sequence":"additional","affiliation":[{"name":"Solid Tumor Immunology Research Rotterdam (STIRR) Group, Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine van","family":"Montfoort","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1461-6725","authenticated-orcid":false,"given":"Casper W. F. van","family":"Eijck","sequence":"additional","affiliation":[{"name":"Solid Tumor Immunology Research Rotterdam (STIRR) Group, Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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