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Immune checkpoint inhibitors (ICIs) are currently not indicated for patients with PDAC except for those with high microsatellite instability. In this study, we developed an immunocompetent orthotopic transplant mouse model with\n                    <jats:italic>Kras<\/jats:italic>\n                    and\n                    <jats:italic>Trp53<\/jats:italic>\n                    mutations, characterized by high fibrosis and an immunosuppressive tumor microenvironment, closely mimicking human PDAC lesions. This model provides a robust platform for investigating strategies for improving ICI efficacy. We observed that ICI monotherapy yielded minimal efficacy, whereas anti\u2010CD40 agonist antibody (aCD40) monotherapy prolonged survival despite its low impact on primary tumor volume. Moreover, ICIs + aCD40 combination therapy not only extended survival but also significantly reduced tumor burden. These effects were accompanied by enhanced dendritic cell migration to the lymph nodes and T cell priming and activation. Moreover, the expression of immunosuppressive markers in tumor\u2010associated macrophages was decreased. Indeed, gene expression analyses of infiltrating immune cells have revealed a shift in the tumor microenvironment from an immune\u2010tolerant state to an immune\u2010activated state. Our findings suggest that combination therapy with ICIs and aCD40 is a promising treatment strategy for patients with PDAC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70246","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T02:59:59Z","timestamp":1762829999000},"page":"8-18","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Combinatorial Effect of Immune Checkpoint Inhibitors and\n                    <scp>CD40<\/scp>\n                    Agonistic Antibody in Murine Pancreatic Cancer Model"],"prefix":"10.1111","volume":"117","author":[{"given":"Juri","family":"Ichikawa","sequence":"first","affiliation":[{"name":"Department of Immunology Yokohama City University Graduate School of Medicine  Kanagawa 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