Abstract
Patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) predominantly receive chemotherapy, and despite initial responses in some patients, most will have disease progression and often dismal outcomes. This lack of clinical effectiveness partly reflects not only cancer cell-intrinsic factors but also the presence of a tumour microenvironment (TME) that precludes access of both systemic therapies and circulating immune cells to the primary tumour, as well as supporting the growth of PDAC cells. Combined with improved preclinical models of PDAC, advances in single-cell spatial multi-omics and machine learning-based models have provided novel methods of untangling the complexities of the TME. In this Review, we focus on the desmoplastic stroma and both the intratumoural and intertumoural heterogeneity of PDAC, with an emphasis on cancer-associated fibroblasts and their surrounding immune cell niches. We describe new approaches in converting the immunologically ‘cold’ PDAC TME into a ‘hot’ TME by priming T cell activation, overcoming T cell exhaustion and unravelling myeloid cell-mediated immunosuppression. Furthermore, we explore integrated targets involving the TME, such as points of convergence among tumour, stromal and immune cell metabolism as well as oncogenic KRAS signalling. Finally, building on our experience with failed clinical trials in the past, we consider how this evolving comprehensive understanding of the TME will ensure future success in developing more effective therapies for patients with PDAC.
Key points
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Heterogeneity within the pancreatic ductal adenocarcinoma (PDAC) tumour microenvironment (TME) is highlighted by differences in both the structure and cellular origin of fibrillar collagen present within the extracellular matrix, with distinct tumour-promoting and tumour-restraining roles.
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Given the heterogeneity and plasticity of cancer-associated fibroblasts in the PDAC TME, research efforts have focused on elucidating the specific tumour-permissive and tumour-restrictive functions of these different subpopulations and targeting them with highly specific therapeutic interventions.
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Cancer-associated fibroblast function is greatly dependent on the specific niche and cellular neighbourhood, and advances in multi-omic, spatial analysis technologies have enabled assessments of the spatial relationships and inference of cellular interactions between neoplastic and stromal components with validation in in vitro models.
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Therapeutic cancer vaccines are capable of presenting PDAC-associated antigens to the immune system to mount an antitumour effector T cell response, including by converting an immunologically ‘cold’ TME into a ‘hot’ one.
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Future research efforts should focus on reprogramming immunosuppressive myeloid cells in the immune TME to prevent T cell exhaustion and sustain effector T cell activation.
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The potential of TME remodelling to bypass dependencies on mutant KRAS supports the further exploration of strategies targeting the TME in combination with, or following KRAS inhibitors to overcome resistance to these agents.
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Change history
13 October 2025
In the version of the article initially published, the name of peer reviewer P. Phillips appeared incorrectly (as Philips) and has now been corrected in the HTML and PDF versions of the article.
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Acknowledgements
The work of L.Z. is supported by National Institutes of Health grants R01CA169702, R01CA197296 and P01CA247886; National Cancer Institute Specialized Programs of Research Excellence in Gastrointestinal Cancers grant P50 CA062924; Sidney Kimmel Comprehensive Cancer Center grant P30 CA006973 and Mays Cancer Center grant P30 CA054174.
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H.-C.K., K.W.Z. and L.Z. researched data for the manuscript. H.-C.K. and L.Z. made substantial contributions to discussions of content. H.-C.K., J.W.Z. and L.Z. wrote the manuscript and reviewed and/or edited before submission.
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L.Z. has acted as a consultant and/or adviser of Akrevia/Xilio, Alphamab, Amberstone, Ambrx Biosion, Clinicaltrial Option, Duo Oncology, Fortress Biotech, Histosonics, Mingruizhiyao, NovaRock, QED and Tavotek, has received research funding from Abmeta, AstraZeneca, Bristol-Meyer Squibb and Merck and holds shares in Alphamab, Amberstone, Cellaration and Mingruizhiyao. J.W.Z. has received research funding from Roche Genentech. The other authors declare no competing interests.
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Kung, HC., Zheng, K.W., Zimmerman, J.W. et al. The tumour microenvironment in pancreatic cancer — new clinical challenges, but more opportunities. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01077-z
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DOI: https://doi.org/10.1038/s41571-025-01077-z
