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[https://doi.org/10.1007/s12029-025-01](https://doi.org/10.1007/s12029-025-01)165-4  \nAdvances in Vaccine‑Based Therapies for Pancreatic Cancer  \nMatthew T. McMillan1,2 · Kevin C. Soares1,2  \nAccepted: 1 January 2025 © The Author(s) 2025  \nAbstract  \nPancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a 5-year survival rate that has improved only marginally over the past 30 years, despite numerous clinical trials. PDAC poses several unique challenges, including early metastatic spread and a predilection for liver metastasis. It is also highly resistant to anti-tumor immunity and immunotherapy due to its dense and immunosuppressive tumor microenvironment, low immunogenicity, and systemic immune suppression. PDAC has a low mutational burden, defective antigen presentation, and immune checkpoint molecule upregulation, which reduce immune recognition. Together, these factors leave PDAC as an “immune cold” tumor with minimal cytotoxic T-cell activity. Novel therapeutic approaches are urgently needed to reinvigorate anti-tumor immunity. Recent advances, such as adjuvant personalized mRNA neoantigen vaccines and mutant-KRAS targeted vaccines, have demonstrated sustained vaccine-induced T cell responses that are associated with improved recurrence-free survival in surgically resected PDAC. Combining different vaccine approaches with optimal sequencing of chemotherapy, surgery, radiotherapy, and other immunotherapies may further enhance outcomes. PDAC vaccines represent a promising strategy for overcoming PDAC’s resistance to conventional therapies, with ongoing trials exploring their potential to improve long-term survival.  \nKeywords MRNA vaccination · Pancreatic cancer · Pancreatic ductal adenocarcinoma · PDAC · Vaccine-based therapies  \nIntroduction  \nPancreatic ductal adenocarcinoma (PDAC) is the tenth most common cancer in the USA and the third leading cause of cancer-related mortality in the USA [1] . Despite > 2000 interventional clinical trials over the past 30 years—including nearly 250 phase III randomized trials—the 5-year relative survival has only increased from 5 to 13%[2] . The majority of immunotherapy breakthroughs in oncology over the past decade have involved immune checkpoint blockade (ICB), which has improved survival outcomes for many immunogenic solid tumor histologies (e.g., melanoma, lung cancer, urothelial carcinoma), including subgroups of patients with immunologically “cold” solid  \n* Kevin C. Soares [soaresk@mskcc.org](soaresk@mskcc.org)  \n1 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA  \n2 Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School, 1275 York Ave, C887, New York, NY 10065, USA  \ntumor histologies who have high microsatellite instability (MSI-H), DNA mismatch-repair deficiency (dMMR), and/or high tumor mutational burden [3–6]. However, this subgroup of patients accounts for \u003C 2% of all PDAC patients, and the ICB (e.g., anti-programmed death-ligand 1 [PD-L1] ± anticytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) response rate in unselected PDAC patients is \u003C 5%[7] . The major challenges to improving survival in PDAC can be distilled down to an immunosuppressive tumor microenvironment (TME) (Fig. 1), few tumor-reactive T cells, and early metastatic dissemination, especially to the liver, which is a tolerogenic organ.  \nThe PDAC TME is profoundly immunosuppressive, harboring regulatory T cells, M2-polarized tumor-associated macrophages, tumor-associated neutrophils, and myeloidderived suppressor cells [8] . These cells release high levels of immunosuppressive cytokines such as TGF-β, IL-10, and VEGF thereby dampening immune responses. The TME also presents a fibrotic stroma composed of cancer-associated fibroblasts, extracellular matrix, and hyaluronic acid. This stroma may act as a physical barrier,","cbCaiiWteFYdOKzA","https://ap.wps.com/l/cbCaiiWteFYdOKzA","pdf",1071261,14,"English","# Abstract\n# Introduction","[{\"question\":\"Why is pancreatic ductal adenocarcinoma (PDAC) resistant to immunotherapy?\",\"answer\":\"PDAC is highly resistant due to its dense, immunosuppressive tumor microenvironment, low immunogenicity, systemic immune suppression, low mutational burden, defective antigen presentation, and immune checkpoint upregulation.\"},{\"question\":\"What does the article mean by PDAC being an “immune cold” tumor?\",\"answer\":\"It refers to minimal cytotoxic T-cell activity resulting from factors that reduce immune recognition, including immune evasion within the tumor microenvironment and systemic immune suppression.\"},{\"question\":\"Which vaccine approaches are highlighted as recent advances for PDAC?\",\"answer\":\"The article highlights adjuvant personalized mRNA neoantigen vaccines and mutant-KRAS targeted vaccines, which have demonstrated sustained vaccine-induced T-cell responses associated with improved recurrence-free survival after surgical resection.\"}]","Advances in Vaccine-Based Therapies for Pancreatic Cancer | PDF",1790201190,35]