Pancreatic ductal adenocarcinoma (PDAC) is a complex disease characterized by high levels of cellular heterogeneity and pronounced microenvironmental remodelling. Dynamic changes during its initiation and progression contribute to resistance to conventional therapies. Building upon key molecular catalogues established by bulk and single-cell profiling studies that have advanced our understanding of PDAC biology, recent advances in spatial biology have provided much-needed insights by elucidating regionally compartmentalized transcriptomic and proteomic programmes within the PDAC microenvironment. In parallel, emerging computational frameworks in digital pathology and artificial intelligence have advanced the field into a high-dimensional, quantitative discipline, particularly for classifying molecular and clinical features from histopathology images. Despite these advancements, integration of these two modalities remains a major challenge. Here, we summarize the convergence of molecular features identified through spatially resolved profiling in PDAC and its precursor lesions, as well as current developments in AI-powered pathology in cancer research. We further propose a multi-modal integration framework that maps molecular states onto morphological and architectural phenotypes, offering a roadmap for spatially informed patient stratification beyond descriptive tissue characterization. We posit that the path forward relies on disciplined cross-scale integration of spatial, histological, and clinical data to ensure meaningful translation into clinical practice. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, often diagnosed late and resistant to treatment. This review highlights emerging evidence from spatial profiling studies demonstrating that PDAC and its precursor lesions are not just a simple mixture of malignant and stromal cells but rather a structured ecosystem with spatially distinct immune and fibroblast niches. Digital pathology and artificial intelligence offer promising complementary approaches to extending insights gained from spatial omics to larger patient cohorts, with the potential to improve risk stratification, prognostic prediction and assessment of therapeutic response. Future research should focus on establishing ground-truth characteristics in different disease contexts in the pancreas and expanding spatially resolved datasets across diverse PDAC cohorts to enable robust development of computational frameworks and improve their clinical applications.
S. Bae, A. Tsirigos, Jimin Min et al.· Experimental and Molecular M...· 0 citations
Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications. Kras mutations have been associated with immune suppression in pancreatic cancer. Here the authors show that KRAS targeting with MRTX1133 or Daraxonrasib specifically synergizes with anti-CTLA4, but not other immune checkpoint inhibitors, in inducing tertiary lymphoid structures and promoting anti-tumor immune responses in preclinical pancreatic cancer models.
Krishnan K. Mahadevan, Ana S Maldonado, Bingrui Li et al.· Nature Communications· 0 citations
By integrating adaptive response to KRAS inhibition with anti-tumor immunity, AXL represents a mechanistically actionable vulnerability whose inhibition deepens and prolongs responses to both allele-specific and pan-KRAS-targeted therapies.
F. Thege, A. Kramer, Norbert Kreisz et al.· bioRxiv· 0 citations
Mediator complex kinase CDK8 is identified as a driver of resistance towards KRASG12D inhibition in pancreatic ductal adenocarcinoma (PDAC), promoting stromal remodeling and immunosuppression and CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy.
Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li et al.· EMBO Journal· 1 citation
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