ArticleGastroenterology2022
Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.
Article in Gastroenterology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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Who cites it
110 citing papers in PubMed, 144 citations in OpenAlex.
- Immune-stromal interactions at the crossroads of tissue injury, repair, and tumor progression.Med (New York, N.Y.) · 2026Review
- A pancreatic cancer organoid-macrophage co-culture using starPEG-heparin hydrogel deciphers tumor-immune cell interactions.NPJ precision oncology · 2026Article
- CAFs shape the immunosuppressive microenvironment of pancreatic cancer through the Lin28b-STING Axis.Nature communications · 2026Article
- HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?Acta pharmaceutica Sinica. B · 2026Review
- The Role of AP-1 in Cancer: Regulation, Tumor Microenvironment and Therapeutic Targeting.Biomolecules · 2026Review
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- Review
- Bidirectional crosstalk between cancer-associated fibroblasts and tumor immunity: shaping the microenvironment and response to immune checkpoint therapy.Experimental hematology & oncology · 2026Review
- Review
- Hypoxic Tumor Microenvironment Targeting: Opportunities and Challenges for Pancreatic Cancer Immunotherapy.International journal of molecular sciences · 2026Review
- The RNA methylation modification as an immunometabolic regulatory hub in pancreatic cancer: from mechanistic insights to clinical translation perspectives.Molecular cancer · 2026Review
- Serial Thermal Ablation Induces Abscopal Antitumor Immunity and Reveals Targetable CSF1R-Dependent Resistance in Pancreatic Cancer.bioRxiv : the preprint server for biology · 2026Article
- The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer.Molecular cell · 2026Article
- Heterogeneity and plasticity of cancer-associated fibroblasts.Nature cancer · 2026Review
- USP10 regulates HIF2α stability by deubiquitinating HIF2α regardless ofTranslational andrology and urology · 2026Article
- Emerging Chimeric Antigen Receptor-Immune Cell Therapy for Pancreatic Cancer: Mechanisms, Clinical Advances, and Future Perspectives.Oncology research · 2026Review
- Radiogenomics and the DNA damage response: opportunities for biomarker-guided radiosensitization in pancreatic cancer.Frontiers in oncology · 2026Review
- Cancer-associated fibroblasts: central players in cancer hallmarks and therapeutic resistance.Cell communication and signaling : CCS · 2025Review
- Harnessing the power of cancer-associated fibroblasts to revolutionize pancreatic cancer treatment.Cancer biology & medicine · 2025Review
- CDKN1A and cellular senescence are associated with immune resistance in advanced lung adenocarcinoma.Clinical and experimental medicine · 2025Article
50 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors at 3 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsPancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown.
methodsWe used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade.
resultsCAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models.
conclusionsTogether, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
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