2. Academic Validation
  3. Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer

Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer

  • Cancer Cell. 2025 Sep 8;43(9):1677-1696.e15. doi: 10.1016/j.ccell.2025.06.021.
Yijuan Zhang 1,  Li Ling 1,  Rabi Murad 2,  Swetha Maganti 1,  Ambroise Manceau 1,  Hannah A Hetrick 1,  Madelaine Neff 1,  Cheska Marie Galapate 1,  Shea F Grenier 1,  Florent Carrette 1,  Karen Duong-Polk 1,  Anindya Bagchi 3,  David A Scott 4,  Yoav Altman 5,  Jennifer L Hope 1,  Andrew M Lowy 6,  Linda M Bradley 1,  Cosimo Commisso 7
Affiliations

Affiliations

  • 1 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 2 Bioinformatics Core Resource, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 3 Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 4 Cancer Metabolism Core Resource, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 5 Flow Cytometry Core Resource, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 6 Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
  • 7 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: ccommisso@sbpdiscovery.org.
PMID: 40712568 DOI: 10.1016/j.ccell.2025.06.021
Abstract

Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis in vivo promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition-including iCAF enrichment, Collagen reduction, immune cell infiltration, and vascular expansion-sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.

Keywords

CAF heterogeneity; chemotherapy; drug delivery; immunotherapy; macropinocytosis; metabolic stress; pancreatic cancer; plasticity; stromal architecture; tumor microenvironment.

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