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A major review by researchers at Trinity College Dublin has brought fresh clarity to pancreatic cancer by mapping how the disease operates across multiple biological systems, rather than through a single pathway or target.
A team at Trinity College Dublin, Ireland, has published a major review that sets out why pancreatic cancer remains one of the most difficult cancers to detect, treat and control. The paper has examined the disease through the most recent ‘Hallmarks of Cancer’ framework, a widely used model that describes the essential biological capabilities acquired by cancer cells as tumours develop and progress.
Broadly speaking, the Hallmarks of Cancer methodology examines these six characteristics:
Pancreatic cancer has the poorest survival rate of any major cancer, with only 13 per cent of patients alive five years after diagnosis. Progress has remained slow because the disease is often detected late, develops aggressively, has limited treatment options and has historically attracted less research funding than some other major cancers. Its biology also makes it unusually resistant to many conventional approaches, because malignant cells operate within a dense and highly active tumour environment that can limit drug access, suppress immune attack and support tumour growth.
Scientists at the Trinity St James’s Cancer Institute – the first comprehensive cancer centre in Ireland – have taken a broad systems-based approach to the disease. Rather than focus on one biological mechanism, the researchers assembled what they described as a ‘comprehensive playbook’ of pancreatic cancer, to show how multiple processes interact to drive tumour development and treatment resistance.
The paper applied the Hallmarks of Cancer framework to pancreatic cancer in exceptional detail. The model was first developed in the year 2,000 by Dr. Douglas Hanahan of the Swiss Institute for Experimental Cancer Research at the École polytechnique fédérale de Lausanne, in Switzerland, and Dr. Robert Weinberg of Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, USA.
The framework offers a general model for cancer biology but the Trinity researchers used it to examine the specific mechanisms that make pancreatic cancer so lethal. These include genetic mutations, changes in tumour metabolism, evasion of the immune system, the tumour microenvironment, tumour–nerve interactions and possible effects from the microbiome.
The review drew together findings from hundreds of studies across these fields. Its central message was that pancreatic cancer should not be understood as a single biological problem. Instead, it is driven by a complex network of mutually reinforcing processes. This helps to explain why therapies that target one pathway alone have often failed to produce substantial survival gains.
“Pancreatic cancer is not driven by one pathway; it’s a highly coordinated system. What we’ve done is bring all of that complexity together into a single, usable framework.
“By showing how these different mechanisms connect, we can start to see where the real vulnerabilities of the disease may lie,” said Dr Laura Kane, lead author of the review and a Research Ireland postdoctoral research fellow.
The review has moved beyond a summary of existing research by identifying areas where scientific understanding is strongest, where significant gaps remain and where future research efforts should be concentrated. The authors argued that single-drug strategies are unlikely to be sufficient for a disease with such interconnected biology. Instead, they suggested that future progress will depend on more rational combination treatments designed to target several hallmarks of the disease at once.
This shift could have important implications for the design of randomised clinical trials (RCTs). In particular, biomarker-led trials may help to identify which patients are most likely to benefit from particular treatment combinations. Biomarkers are measurable biological features, such as genetic mutations or molecular signatures, that can help clinicians to classify disease more precisely and match treatment to tumour biology.
The authors also emphasised the need for better laboratory models that more accurately reflect the complexity of real pancreatic tumours. Conventional laboratory systems often fail to reproduce the dense stromal tissue, immune activity, metabolic stress and cellular diversity found in patients at the clinic. More faithful models could make it easier to test novel therapeutic combinations before they enter RCTs.
“Despite decades of research, outcomes for pancreatic cancer patients have improved only marginally. This paper helps explain why. It also provides a roadmap for designing the next generation of treatments, ones that reflect the true complexity of the disease,” said Professor Stephen Maher, senior author of the review and professor in translational oncology.
The review is particularly relevant for clinicians and cancer researchers but it also offers a clearer explanation for patients and families who want to understand why pancreatic cancer has proved so resistant to treatment. By setting out how its biological systems interact, the work points to where more effective therapeutic strategies may emerge.
The researchers concluded that future advances are likely to depend on more integrated approaches to pancreatic cancer biology. These may include biomarker-led treatment selection, improved tumour models, rational drug combinations and RCTs designed around the full complexity of the disease rather than single mechanisms alone.
By drawing together evidence across several fields, the review has provided one of the most comprehensive recent overviews of pancreatic cancer and has outlined a clearer path towards more effective treatments.
For further reading please visit: 10.1016/j.canlet.2026.218437
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