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Peer-reviewedCC BY-NC-ND 4.0Nature

A serpin–myeloid axis in pancreatic cancer heterogeneity and immune evasion

  • Chiara Falcomatà1,2
  • Maximilian M. Schaefer1,2
  • Bhavya Singh1,2
  • Divya Chhamalwan1,2
  • Alexander Tepper1,2
  • Sebastian R. Nielsen1,2
  • Hunter T. Potak1,2
  • Maxime Dhainaut1,2
  • Gurkan Mollaoglu1,2,3,4
  • Matthew D. Park2,3,4
  • Miriam Merad2,3,4
  • Alessia Baccarini1,2,4
1 more authors
  • Brian D. Brown1,2,3,4
4 affiliations
  1. 1Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
  2. 2Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
  3. 3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
  4. 4Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY USA
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Abstract

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1–4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

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Cite

BibTeXRIS
BibTeX
@article{falcomata2026serpinmyeloid,
  title = {{A serpin–myeloid axis in pancreatic cancer heterogeneity and immune evasion}},
  author = {Chiara Falcomatà and Maximilian M. Schaefer and Bhavya Singh and Divya Chhamalwan and Alexander Tepper and Sebastian R. Nielsen and Hunter T. Potak and Maxime Dhainaut and Gurkan Mollaoglu and Matthew D. Park and Miriam Merad and Alessia Baccarini and Brian D. Brown},
  journal = {Nature},
  year = {2026},
  month = sep,
  doi = {10.1038/s41586-026-11002-8},
  url = {https://doi.org/10.1038/s41586-026-11002-8},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A serpin–myeloid axis in pancreatic cancer heterogeneity and immune evasion
AU  - Chiara Falcomatà
AU  - Maximilian M. Schaefer
AU  - Bhavya Singh
AU  - Divya Chhamalwan
AU  - Alexander Tepper
AU  - Sebastian R. Nielsen
AU  - Hunter T. Potak
AU  - Maxime Dhainaut
AU  - Gurkan Mollaoglu
AU  - Matthew D. Park
AU  - Miriam Merad
AU  - Alessia Baccarini
AU  - Brian D. Brown
PY  - 2026
DA  - 2026/09/09
JO  - Nature
DO  - 10.1038/s41586-026-11002-8
UR  - https://doi.org/10.1038/s41586-026-11002-8
AB  - Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1–4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.
SN  - 0028-0836
SN  - 1476-4687
ER  -