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From Standard of Care to mRNA Cancer Vaccines and Spatial Architecture-Based Precision Therapy in PDAC: Challenges and Expectations
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Centre for Biosystems and Genome Medicine, Ioannina University, 45110 Ioannina, Greece
2
First Department of Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(11), 1824; https://doi.org/10.3390/cancers18111824
Submission received: 21 April 2026
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Revised: 19 May 2026
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Accepted: 28 May 2026
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Published: 2 June 2026
(This article belongs to the Special Issue Pancreatic Cancer: Clinical Standards, Unmet Needs and Future Directions)
Simple Summary
Pancreatic ductal adenocarcinoma (PDAC), with a 5-year overall survival of 13%, represents the challenge of the future. Despite surgical resection, the cornerstone of treatment, being feasible in only 20% of patients, with neoadjuvant and/or adjuvant modern chemotherapy, recurrence and mortality rates remain very high. Research efforts to combine chemotherapy with immune checkpoint inhibitors and targeted therapy have not yet translated into clinical practice. We describe the latest advances in the standard of care and the unmet needs to be overcome. Personalized mRNA cancer vaccines and circulating tumor DNA-based minimal residual disease detection to predict recurrence have rapidly translated into randomized clinical trials, holding promises to improve outcomes. Even greater expectations are provided by the unprecedented potential of innovative research integrating single-cell spatial multiomics, artificial intelligence, and systems biology to understand the extraordinarily complex and dynamically evolving PDAC tumor microenvironment. These advances constitute the hope of the future through the discovery of novel biomarkers guiding optimization of immune-based therapy, combinatorial treatment, tailored to individual patients.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most complex and aggressive disease with the worst rates of unresectable or metastatic disease at diagnosis, resistance to systemic therapy, and case fatality rate (CFR) among leading cancers. In non-metastatic disease, neoadjuvant treatment with modern chemotherapeutic regimens followed by surgical resection and/or adjuvant mFOLFIRINOX has significantly improved oncological outcomes. However, recurrence rates remain alarmingly high, while immune checkpoint inhibitors (ICIs) or molecularly targeted therapy have not yet demonstrated clinical benefits. Comprehensive genomic profiling through NGS-based approved assays such as TruSight Oncology 500 (TSO500) could guide targeted therapy. Rapidly evolving mRNA cancer vaccines and circulating tumor DNA (ctDNA)-based prediction of minimal residual disease (MRD) and recurrence risk hold great promise towards the realization of rational combination therapy to improve recurrence-free survival (RFS) and overall survival (OS). More recently, single-cell multiomics (SC MO), spatial proteomics and transcriptomics (SPT), artificial intelligence (AI), and systems biology have revolutionized cancer research, enabling holistic tumor microenvironment (TME) analysis. In this comprehensive review, we describe the latest advances and unmet needs in the standard of care of PDAC. Moreover, we discuss the expectations of ongoing randomized clinical trials of adjuvant mRNA vaccine-based therapy and ctDNA MRD testing as prognostic biomarkers, towards personalized treatment to improve RFS and OS in a medium-term perspective. With a longer perspective, we explore how harnessing SC MO, SPT, AI, and systems biology can reveal the 3D spatial organization of interacting cancer, immune, and stromal cells. Multi-dimensional TME-, TSO500- and ctDNA-based framework of dynamic biomarkers are of paramount importance to achieve an optimal patient-specific perioperative multimodal treatment combining precision immunotherapy, targeted drugs, and modern chemotherapy, translated into future practice-changing clinical trials, that could eliminate MRD towards recurrence prevention.
