Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses

Nature Immunology volume 26, pages 2138–2147 (2025)Cite this article

Subjects

Abstract

Oxygen availability and fluctuation are common changes in tissues and organs undergoing infection and damage. While acute hypoxia can rapidly alter immune cell metabolism and activity, chronic hypoxia can induce long-lasting changes in immune responses via oxygen-guided adaptation in signaling cascades and epitranscriptomic programs. These adaptations are orchestrated mainly by oxygen-sensing hydroxylases and oxygen-sensing epigenetic modifiers that regulate downstream hypoxia-inducible factor pathways and epigenetic reprogramming. In this Review, we summarize how acute and chronic hypoxia influence innate immune cell function and metabolism, thereby tailoring immune cell behavior within the tissue microenvironment. We further highlight the dual roles of hypoxia in regulating innate immune cell function in different (patho)physiological contexts and evaluate therapeutic strategies that target oxygen-sensing pathways to restore immune competence and tissue homeostasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of oxygen sensing.
Fig. 2: Influence of acute hypoxia on immune cells during inflammation.
Fig. 3: Myeloid cell adaptation to hypoxia in the fibrotic microenvironment and the TME.

Similar content being viewed by others

References

  1. McKeown, S. R. Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response. Br. J. Radiol. 87, 20130676 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Zheng, L., Kelly, C. J. & Colgan, S. P. Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A review in the theme: cellular responses to hypoxia. Am. J. Physiol. Cell Physiol. 309, C350–C360 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269–273 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5, 343–354 (2004).

    Article  PubMed  CAS  Google Scholar 

  5. Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Mole, D. R. Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid. Redox Signal. 12, 445–458 (2010).

    Article  PubMed  CAS  Google Scholar 

  8. Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Brunelle, J. K. et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab. 1, 409–414 (2005).

    Article  PubMed  CAS  Google Scholar 

  10. Mahon, P. C., Hirota, K. & Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    Article  PubMed  CAS  Google Scholar 

  12. Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Piccolo, E. B. et al. Hypoxia-inducible factor-2α enhances neutrophil survival to promote cardiac injury following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 327, H1230–H1243 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Heikkila, M., Pasanen, A., Kivirikko, K. I. & Myllyharju, J. Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response. Cell. Mol. Life Sci. 68, 3885–3901 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    Article  PubMed  CAS  Google Scholar 

  16. Wenger, R. H., Stiehl, D. P. & Camenisch, G. Integration of oxygen signaling at the consensus HRE. Sci. STKE 2005, re12 (2005).

    Article  PubMed  Google Scholar 

  17. Koivunen, P., Hirsila, M., Gunzler, V., Kivirikko, K. I. & Myllyharju, J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279, 9899–9904 (2004).

    Article  PubMed  CAS  Google Scholar 

  18. Gao, R. Y. et al. Hypoxia-inducible factor-2α reprograms liver macrophages to protect against acute liver injury through the production of interleukin-6. Hepatology 71, 2105–2117 (2020).

    Article  PubMed  CAS  Google Scholar 

  19. Li, L., et al. Searching for molecular hypoxia sensors among oxygen-dependent enzymes. eLife 12, e87705 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019).

    Article  PubMed  CAS  Google Scholar 

  21. Wu, H. & Zhang, Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156, 45–68 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Tarhonskaya, H. et al. Investigating the contribution of the active site environment to the slow reaction of hypoxia-inducible factor prolyl hydroxylase domain 2 with oxygen. Biochem. J. 463, 363–372 (2014).

    Article  PubMed  CAS  Google Scholar 

  25. Thienpont, B. et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537, 63–68 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).

    Article  PubMed  CAS  Google Scholar 

  27. Campbell, E. L. et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kominsky, D. J., Campbell, E. L. & Colgan, S. P. Metabolic shifts in immunity and inflammation. J. Immunol. 184, 4062–4068 (2010).

    Article  PubMed  CAS  Google Scholar 

  29. Holmstrom, K. M. & Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 15, 411–421 (2014).

    Article  PubMed  CAS  Google Scholar 

  30. Burn, G. L., Foti, A., Marsman, G., Patel, D. F. & Zychlinsky, A. The neutrophil. Immunity 54, 1377–1391 (2021).

    Article  PubMed  CAS  Google Scholar 

  31. Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).

    Article  PubMed  CAS  Google Scholar 

  32. Walmsley, S. R. et al. Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J. Exp. Med. 201, 105–115 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Hoenderdos, K. et al. Hypoxia upregulates neutrophil degranulation and potential for tissue injury. Thorax 71, 1030–1038 (2016).

    Article  PubMed  Google Scholar 

  34. Sadiku, P. et al. Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. J. Clin. Invest. 127, 3407–3420 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Pescador, N., et al. Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. PLoS ONE 5, e9644 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sadiku, P. et al. Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis. Cell Metab. 33, 411–423 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Watts, E. R., et al. Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism. J. Clin. Invest. 131, e134073 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Mancino, A. et al. Divergent effects of hypoxia on dendritic cell functions. Blood 112, 3723–3734 (2008).

    Article  PubMed  CAS  Google Scholar 

  40. Bosco, M. C. et al. Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood 117, 2625–2639 (2011).

    Article  PubMed  CAS  Google Scholar 

  41. Cummins, E. P. et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134, 156–165 (2008).

    Article  PubMed  CAS  Google Scholar 

  42. Robinson, A. et al. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134, 145–155 (2008).

    Article  PubMed  CAS  Google Scholar 

  43. Lee, J. W., Ko, J., Ju, C. & Eltzschig, H. K. Hypoxia signaling in human diseases and therapeutic targets. Exp. Mol. Med. 51, 1–13 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bobrow, B., et al. Identification of HIF1A as a therapeutic target during SARS-CoV-2-associated lung injury. JCI Insight 10, e191463 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pral, L. P., Fachi, J. L., Correa, R. O., Colonna, M. & Vinolo, M. A. R. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. Trends Immunol. 42, 604–621 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Koeppen, M. et al. Hypoxia-inducible factor 2-α-dependent induction of amphiregulin dampens myocardial ischemia–reperfusion injury. Nat. Commun. 9, 816 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ruan, W. et al. BMAL1–HIF2A heterodimer modulates circadian variations of myocardial injury. Nature 641, 1017–1028 (2025).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Eltzschig, H. K., Sitkovsky, M. V. & Robson, S. C. Purinergic signaling during inflammation. N. Engl. J. Med. 367, 2322–2333 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Colgan, S. P. & Eltzschig, H. K. Adenosine and hypoxia-inducible factor signaling in intestinal injury and recovery. Annu. Rev. Physiol. 74, 153–175 (2012).

    Article  PubMed  CAS  Google Scholar 

  50. Eltzschig, H. K. et al. ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ. Res. 99, 1100–1108 (2006).

    Article  PubMed  CAS  Google Scholar 

  51. Synnestvedt, K. et al. Ecto-5’-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Eltzschig, H. K. et al. Central role of Sp1-regulated CD39 in hypoxia/ischemia protection. Blood 113, 224–232 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Eckle, T. et al. Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. J. Immunol. 178, 8127–8137 (2007).

    Article  PubMed  CAS  Google Scholar 

  54. Kong, T., Westerman, K. A., Faigle, M., Eltzschig, H. K. & Colgan, S. P. HIF-dependent induction of adenosine A2B receptor in hypoxia. FASEB J. 20, 2242–2250 (2006).

    Article  PubMed  CAS  Google Scholar 

  55. Eckle, T. et al. Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J. Immunol. 192, 1249–1256 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Rosenberger, P. et al. Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat. Immunol. 10, 195–202 (2009).

    Article  PubMed  CAS  Google Scholar 

  57. Ly, N. P. et al. Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc. Natl Acad. Sci. USA 102, 14729–14734 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Ramkhelawon, B. et al. Hypoxia induces netrin-1 and Unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival. Arterioscler. Thromb. Vasc. Biol. 33, 1180–1188 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Berg, N. K. et al. Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury. FASEB J. 35, e21334 (2021).

    Article  PubMed  CAS  Google Scholar 

  60. Heck-Swain, K. L. et al. Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1. Front. Cardiovasc. Med. 9, 970415 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Buckley, C. D., Gilroy, D. W., Serhan, C. N., Stockinger, B. & Tak, P. P. The resolution of inflammation. Nat. Rev. Immunol. 13, 59–66 (2013).

    Article  PubMed  CAS  Google Scholar 

  62. Liu, S. et al. The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications. Mol. Cancer 22, 148 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Luo, B. et al. Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution. Nat. Commun. 7, 12177 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Basil, M. C. & Levy, B. D. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat. Rev. Immunol. 16, 51–67 (2016).

    Article  PubMed  CAS  Google Scholar 

  65. Norris, P. C., Libreros, S. & Serhan, C. N. Resolution metabolomes activated by hypoxic environment. Sci. Adv. 5, eaax4895 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810–3820 (2007).

    PubMed  PubMed Central  CAS  Google Scholar 

  67. Younesi, F. S., Miller, A. E., Barker, T. H., Rossi, F. M. V. & Hinz, B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat. Rev. Mol. Cell Biol. 25, 617–638 (2024).

    Article  PubMed  CAS  Google Scholar 

  68. Siddiqui, A. et al. Differential effects of oxygen on human dermal fibroblasts: acute versus chronic hypoxia. Wound Repair Regen. 4, 211–218 (1996).

    Article  PubMed  CAS  Google Scholar 

  69. Yan, S., Li, M., Liu, B., Ma, Z. & Yang, Q. Neutrophil extracellular traps and pulmonary fibrosis: an update. J. Inflamm. 20, 2 (2023).

    Article  CAS  Google Scholar 

  70. Chua, F. et al. Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 170, 65–74 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Rodriguez-Espinosa, O., Rojas-Espinosa, O., Moreno-Altamirano, M. M., Lopez-Villegas, E. O. & Sanchez-Garcia, F. J. Metabolic requirements for neutrophil extracellular traps formation. Immunology 145, 213–224 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Frangogiannis, N. Transforming growth factor-β in tissue fibrosis. J. Exp. Med. 217, e20190103 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ikeda, N., et al. Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury. Sci. Immunol. 3, eaat0207 (2018).

    Article  PubMed  Google Scholar 

  74. Ingersoll, M. A., Platt, A. M., Potteaux, S. & Randolph, G. J. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 32, 470–477 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Jiang, Y., et al. Macrophages in organ fibrosis: from pathogenesis to therapeutic targets. Cell Death Discov. 10, 487 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Corcoran, S. E. & O’Neill, L. A. HIF1α and metabolic reprogramming in inflammation. J. Clin. Invest. 126, 3699–3707 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Wang, Y. et al. Hypoxia induces M2 macrophages to express VSIG4 and mediate cardiac fibrosis after myocardial infarction. Theranostics 13, 2192–2209 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Beneke, A. et al. Loss of PHD3 in myeloid cells dampens the inflammatory response and fibrosis after hind-limb ischemia. Cell Death Dis. 8, e2976 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Misharin, A. V. et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. 214, 2387–2404 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Chakraborty, M. et al. Mechanical stiffness controls dendritic cell metabolism and function. Cell Rep. 34, 108609 (2021).

    Article  PubMed  CAS  Google Scholar 

  81. Stefania, K., Ashok, K. K., Geena, P. V., Katarina, P. & Isak, D. TMAO enhances TNF-α mediated fibrosis and release of inflammatory mediators from renal fibroblasts. Sci. Rep. 14, 9070 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Odell, I. D. et al. Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis. Sci. Immunol. 7, eabq6691 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  PubMed  CAS  Google Scholar 

  84. Thomlinson, R. H. Hypoxia and tumours. J. Clin. Pathol. Suppl. (R. Coll. Pathol.) 11, 105–113 (1977).

    Article  PubMed  CAS  Google Scholar 

  85. Paredes, F., Williams, H. C. & San Martin, A. Metabolic adaptation in hypoxia and cancer. Cancer Lett. 502, 133–142 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Yamauchi, M., Barker, T. H., Gibbons, D. L. & Kurie, J. M. The fibrotic tumor stroma. J. Clin. Invest. 128, 16–25 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ding, X. C., et al. The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia. J. Hematol. Oncol. 14, 92 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Franco, F., Jaccard, A., Romero, P., Yu, Y. R. & Ho, P. C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat. Metab. 2, 1001–1012 (2020).

    Article  PubMed  CAS  Google Scholar 

  89. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Di Conza, G. et al. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nat. Immunol. 22, 1403–1415 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Tsai, C. H. et al. Immunoediting instructs tumor metabolic reprogramming to support immune evasion. Cell Metab. 35, 118–133 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).

    Article  PubMed  CAS  Google Scholar 

  94. Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).

    Article  PubMed  CAS  Google Scholar 

  95. Ng, M. S. F. et al. Deterministic reprogramming of neutrophils within tumors. Science 383, eadf6493 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Singhal, R. et al. Disruption of hypoxia-inducible factor-2α in neutrophils decreases colitis-associated colon cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 326, G53–G66 (2024).

    Article  PubMed  Google Scholar 

  97. Quin, C., et al. Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function. J. Clin. Invest. 134, e171002 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Fan, C. et al. Hypoxia promotes the tolerogenic phenotype of plasmacytoid dendritic cells in head and neck squamous cell carcinoma. Cancer Med. 11, 922–930 (2022).

    Article  PubMed  Google Scholar 

  99. Jantsch, J. et al. Hypoxia and hypoxia-inducible factor-1 α modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 180, 4697–4705 (2008).

    Article  PubMed  CAS  Google Scholar 

  100. Traversari, C., Sozzani, S., Steffensen, K. R. & Russo, V. LXR-dependent and -independent effects of oxysterols on immunity and tumor growth. Eur. J. Immunol. 44, 1896–1903 (2014).

    Article  PubMed  CAS  Google Scholar 

  101. Jhunjhunwala, S., Hammer, C. & Delamarre, L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat. Rev. Cancer 21, 298–312 (2021).

    Article  PubMed  CAS  Google Scholar 

  102. Wenes, M. et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 24, 701–715 (2016).

    Article  PubMed  CAS  Google Scholar 

  103. Su, P. et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 80, 1438–1450 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Xu, Z. et al. Scavenger receptor CD36 in tumor-associated macrophages promotes cancer progression by dampening type-I IFN signaling. Cancer Res. 85, 462–476 (2025).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Pathria, P., Louis, T. L. & Varner, J. A. Targeting tumor-associated macrophages in cancer. Trends Immunol. 40, 310–327 (2019).

    Article  PubMed  CAS  Google Scholar 

  106. Liu, P. S. et al. CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions. Nat. Immunol. 24, 452–462 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).

    Article  PubMed  CAS  Google Scholar 

  108. Yuen, C. M. Hyperbaric oxygen therapy as a novel approach to modulating macrophage polarization for the treatment of glioblastoma. Biomedicines 12, 1383 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Kietzmann, T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol. 11, 622–630 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Balmer, M. L., et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl. Med. 6, 237ra266 (2014).

    Article  Google Scholar 

  111. Sleyster, E. C. & Knook, D. L. Relation between localization and function of rat liver Kupffer cells. Lab. Invest. 47, 484–490 (1982).

    PubMed  CAS  Google Scholar 

  112. Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P. & Eltzschig, H. K. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat. Rev. Drug Discov. 23, 175–200 (2024).

    Article  PubMed  CAS  Google Scholar 

  113. Kapitsinou, P. P. et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 116, 3039–3048 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Nagashima, R., Ishikawa, H., Kuno, Y., Kohda, C. & Iyoda, M. HIF–PHD inhibitor regulates the function of group2 innate lymphoid cells and polarization of M2 macrophages. Sci. Rep. 13, 1867 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Hirota, K. HIF-α prolyl hydroxylase inhibitors and their implications for biomedicine: a comprehensive review. Biomedicines 9, 468 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Zeng, M. et al. The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization. J. Mol. Med. 95, 417–429 (2017).

    Article  PubMed  CAS  Google Scholar 

  117. Cowman, S. J. & Koh, M. Y. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer 8, 28–42 (2022).

    Article  PubMed  CAS  Google Scholar 

  118. Hellwig-Burgel, T., Rutkowski, K., Metzen, E., Fandrey, J. & Jelkmann, W. Interleukin-1β and tumor necrosis factor-α stimulate DNA binding of hypoxia-inducible factor-1. Blood 94, 1561–1567 (1999).

    Article  PubMed  CAS  Google Scholar 

  119. Mirchandani, A. S., Sanchez-Garcia, M. A. & Walmsley, S. R. How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia. Nat. Rev. Immunol. 25, 161–177 (2024).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

P.-C.H. is supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Cancer Research Institute (Lloyd J. Old STAR award), the Swiss Cancer League and the Helmut Horten Stiftung.

Author information

Author notes

  1. These authors contributed equally: Jie Ting Low, Youngjun Kim, Mai Matsushita.

Authors and Affiliations

  1. Department of Oncology, University of Lausanne, Lausanne, Switzerland

    Jie Ting Low, Youngjun Kim, Mai Matsushita & Ping-Chih Ho

  2. Ludwig Institute for Cancer Research, University of Lausanne, Épalinges, Switzerland

    Jie Ting Low, Youngjun Kim, Mai Matsushita & Ping-Chih Ho

  3. College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Ping-Chih Ho

Authors
  1. Jie Ting Low
    View author publications

    Search author on:PubMed Google Scholar

  2. Youngjun Kim
    View author publications

    Search author on:PubMed Google Scholar

  3. Mai Matsushita
    View author publications

    Search author on:PubMed Google Scholar

  4. Ping-Chih Ho
    View author publications

    Search author on:PubMed Google Scholar

Contributions

J.T.L. and P.-C.H. contributed to the conceptualization. J.T.L., Y.K., M.M. and P.-C.H. wrote the manuscript.

Corresponding authors

Correspondence to Mai Matsushita or Ping-Chih Ho.

Ethics declarations

Competing interests

P.-C.H. is a cofounder of Pilatus Biosciences.

Peer review

Peer review information

Nature Immunology thanks Navdeep Chandel and the other anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Ioana Staicu, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Low, J.T., Kim, Y., Matsushita, M. et al. Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses. Nat Immunol 26, 2138–2147 (2025). https://doi.org/10.1038/s41590-025-02317-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41590-025-02317-1

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer