Intratumoral hypoxia and mechanisms of immune evasion mediated by hypoxia-inducible factors
Abstract
Activation of the innate and adaptive immune systems represents a promising strategy for defeating cancer. However, during tumor progression, cancer cells battle to shift the balance from immune activation to immunosuppression. Critical sites of this battle are regions of intratumoral hypoxia, and a major driving force for immunosuppression is the activity of hypoxia-inducible factors, which regulate the transcription of large batteries of genes in both cancer and stromal cells that block the infiltration and activity of cytotoxic T lymphocytes and natural killer cells, while stimulating the infiltration and activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Targeting hypoxia-inducible factors or their target gene products may restore anticancer immunity and improve the response to immunotherapies.
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HIFs play critical roles in cancer progression by activating transcription of genes encoding proteins involved in angiogenesis, glucose metabolism, invasion/metastasis, stem cell specification, protumoral inflammatory responses, and tumor immune evasion.
“Hypoxia-inducible factors (HIFs) play critical roles in cancer progression by activating the transcription of a large battery of genes encoding proteins that play key roles in angiogenesis, glucose metabolism, invasion/metastasis, stem cell specification, protumoral inflammatory responses, and tumor immune evasion (18, 23–27).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [25]
It is likely that the poor response rate across all human cancers is due in part to the multiplicity of molecular mechanisms, many of them regulated by HIFs, by which cancer cells evade the immune system.
“It is likely that the poor response rate across all human cancers is due in part to the multiplicity of molecular mechanisms (90), many of them regulated by HIFs (25), by which cancer cells evade the immune system.”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [25]
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- Authors
- Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- ORCID
- Semenza, Gregg L.
- Venue
- Physiology
- Publisher
- American Physiological Society
- Published
- 2021-03-01
- Volume
- 36
- Issue
- 2
- Pages
- 73-83
- ISSN
- 0886-1714 (ISSN-L)
- 1548-9213
- 1548-9221
- OpenAlex
- W3131474805
- Cited by
- 64
- References
- 25
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 12 · 2023: 11 · 2022: 20 · 2021: 4
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Armstrong Family Foundation
- Cindy Rosencrans Foundation
- American Cancer Society (RP-16-239-06-COUN)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- intratumoral hypoxia, hypoxia-inducible factor, tumor immune evasion, immunosuppression, regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, natural killer cells, cytotoxic T lymphocytes, tumor stroma, cancer immunotherapy, transcriptional regulation
- MeSH terms
- Hypoxia, Humans, Neoplasms, Basic Helix-Loop-Helix Proteins, Immune Evasion
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