Hypoxic microenvironment in cancer: role in metabolic reprogramming
Open accessAbstract
Hypoxia, a defining hallmark of solid tumors, arises from structurally and functionally abnormal vasculature, rapid cellular proliferation, and impaired perfusion, resulting in chronic and cycling oxygen deprivation within the tumor massThe hypoxic tumor microenvironment orchestrates extensive molecular reprogramming primarily through stabilization and activation of hypoxia-inducible factors (HIF-1α and HIF-2α), which regulate broad transcriptional networks governing metabolism, angiogenesis, stemness, invasion, and immune modulation. Under low oxygen tension, tumor cells shift toward aerobic glycolysis, enhance glutamine utilization, promote lipid synthesis and storage, suppress mitochondrial oxidative phosphorylation, and fine-tune redox balance through coordinated regulation of ROS-generating and antioxidant systems. These adaptations not only sustain proliferation and survival under metabolic stress but also facilitate epithelial–mesenchymal transition, extracellular matrix remodeling, and metastatic dissemination. Beyond malignant cells, hypoxia reprograms stromal compartments—including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages, and myeloid-derived suppressor cells—thereby establishing a metabolically cooperative, angiogenic, and profoundly immunosuppressive microenvironment. Hypoxia-induced acidosis, lactate accumulation, and HIF-driven cytokine signaling further impair cytotoxic T-cell and NK-cell activity, contributing to immune escape and resistance to radiotherapy, chemotherapy, and immunotherapy. Emerging evidence from single-cell multi-omics, spatial transcriptomics, metabolic imaging, and early-phase clinical trials targeting HIF signaling, angiogenic pathways, and metabolic enzymes has uncovered actionable vulnerabilities in hypoxia-driven malignancies. This review synthesizes the mechanistic foundations of hypoxia-induced metabolic reprogramming, its role in tumor progression and therapeutic resistance, and discusses innovative strategies aimed at exploiting hypoxia-associated metabolic dependencies to advance precision oncology.
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Hypoxia leads to stabilization of HIF-1α, which induces VEGF expression and promotes angiogenesis.
“As tumors grow beyond the reach of blood vessels, hypoxia leads to the stabilization of hypoxia-inducible factor 1α (HIF-1α), which then induces the expression of vascular endothelial growth factor (VEGF) and promotes angiogenesis [54].”
From Overcoming Resistance to Anti-EGFR Therapies: Mechanisms of Cetuximab and Panitumumab Resistance and Emerging Combination Strategies (2026) · cites this paper as [54]
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- Authors
- Sureka, N., Maheshwari, R., Agravat, A., Singhal, S., Zaman, S., Rishi, B., Siraj, F., Zaheer, S., & Misra, A.
- Affiliations
- Safdarjang Hospital (IN)
- Department of Pathology, Pandit Deendayal Upadhyay (PDU) Medical College
- Indian Council of Medical Research (IN)
- National Institute of Child Health (PK)
- Corresponding author
- Zaheer, Sufian
- Misra, Aroonima
- ORCID
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2026-03-31
- Volume
- 16
- Pages
- 1771365-1771365
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC13076347
- OpenAlex
- W7143706570
- Cited by
- 11
- References
- 313
- Citations by year
- 2026: 11
- FWCI
- 9.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor hypoxia, hypoxic tumor microenvironment, metabolic reprogramming, hypoxia-inducible factor, HIF-1α, HIF-2α, aerobic glycolysis, glutamine metabolism, lipid metabolism, redox homeostasis, reactive oxygen species, epithelial-mesenchymal transition, extracellular matrix remodeling, metastasis, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, tumor immunosuppression, immune evasion, treatment resistance, HIF-targeted therapy, precision oncology
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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