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Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a remarkably immunosuppressive tumor microenvironment (TME) and systemic inflammation. This review discusses the potential of both exogenous and in situ vaccination strategies to overcome these barriers and enhance anti-tumor immunity in PDA. Exogenous vaccines, including whole-cell, dendritic cell, peptide, and nucleic acid-based vaccines, have shown varying degrees of promise but face challenges related to antigen selection, production complexities, and patient-specific factors. In contrast, in situ vaccination strategies leverage conventional cytotoxic therapies, such as chemotherapy and radiation therapy, to induce immunogenic cell death and modulate the TME with the aim to stimulate anti-tumor immunity. While preclinical studies support the use of in situ vaccination, balancing the stimulatory and inhibitory effects is likely fundamental to eliciting productive anti-tumor responses in patients. Ongoing research seeks to identify new innovative strategies that can harness the endogenous immune response and trigger in situ vaccination. Overall, while both vaccination approaches offer significant potential, further research and clinical trials will be needed to optimize these strategies for improving patient outcomes in PDA.<\/jats:p>","DOI":"10.1093\/carcin\/bgae065","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T15:20:30Z","timestamp":1730820030000},"page":"826-835","source":"Crossref","is-referenced-by-count":5,"title":["Exogenous or\n                    <i>in situ<\/i>\n                    vaccination to trigger clinical responses in pancreatic cancer"],"prefix":"10.1093","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7165-5993","authenticated-orcid":false,"given":"Gregory L","family":"Beatty","sequence":"first","affiliation":[{"name":"Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine , 3400 Civic Center Blvd, South Pavilion, Rm 8-107, Philadelphia, PA 19104 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-6549","authenticated-orcid":false,"given":"Elizabeth M","family":"Jaffee","sequence":"additional","affiliation":[{"name":"The Sidney Kimmel Comprehensive Cancer Center, The Bloomberg Kimmel Institute for Immunotherapy, The Cancer Convergence Institute, Johns Hopkins University School of Medicine , 4M07 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"2025110905362257600_CIT0001","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1053\/j.gastro.2018.12.038","article-title":"Broadening the impact of immunotherapy to pancreatic cancer: challenges and 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