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Updated: Apr 16, 2026
Tumor Hypoxia Assessment: In Vivo 3D Oxygen Imaging Through Electron Paramagnetic Resonance
Published on: February 14, 2025
Immunological mechanisms of the antitumor effects of supplemental oxygenation
Stephen M Hatfield1, Jorgen Kjaergaard1, Dmitriy Lukashev1
1New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Abstract:
Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell- and natural killer cell-dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer.
Insights
Respiratory hyperoxia combats tumor immunosuppression by reducing hypoxia and adenosine. This approach enhances anti-cancer T cell activity, promoting tumor regression and improving survival in mice.
Area of Science:
- Immunology
- Oncology
- Respiratory Medicine
Background:
- Tumor microenvironments (TMEs) are often hypoxic and rich in adenosine, which inhibits antitumor T cells via A2A adenosine receptors.
- This hypoxia-adenosinergic immunosuppression presents a significant barrier to effective cancer immunotherapy.
- There is a critical need for safe and accessible treatments to overcome this immunosuppressive TME.
Purpose of the Study:
- To investigate whether respiratory hyperoxia can reverse hypoxia-adenosinergic immunosuppression in the TME.
- To evaluate the impact of respiratory hyperoxia on anti-tumor immune responses and tumor regression in preclinical models.
Main Methods:
- Mice bearing lung tumors or spontaneous breast cancer metastases were exposed to respiratory hyperoxia.
- Intratumoral hypoxia, extracellular adenosine levels, T cell infiltration and function, cytokine profiles, and tumor regression were assessed.
- The role of T cells and natural killer cells in mediating the observed effects was investigated.
Main Results:
- Respiratory hyperoxia significantly decreased intratumoral hypoxia and extracellular adenosine concentrations.
- Hyperoxia reversed TME immunosuppression, leading to enhanced CD8 T cell infiltration and activity.
- Increased proinflammatory cytokines and decreased immunosuppressive molecules (e.g., TGF-β) were observed.
- Immune suppression by regulatory T cells was weakened, promoting lung tumor regression and improved survival.
- Spontaneous breast cancer metastasis regression was observed, dependent on T cells and natural killer cells.
Conclusions:
- Respiratory hyperoxia effectively counteracts the immunosuppressive effects of hypoxia and adenosine in the TME.
- Supplemental oxygen acts as an immunological coadjuvant, enhancing endogenous and adoptive T cell-mediated anti-tumor immunity.
- These findings support the clinical investigation of supplemental oxygen as an immunotherapy combination strategy for cancer treatment.
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