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Cited by 13Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer Cells and Metastasis

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Hypoxic microenvironment in cancer: role in metabolic reprogramming

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Sureka, Niti, Maheshwari, Rashi, Agravat, Amit, Singhal, Shweta, Zaman, Shamsuz, Rishi, Bhavika, Siraj, Fouzia, Zaheer, Sufian, Misra, Aroonima·2026·Frontiers in Oncology
DOI 10.3389/fonc.2026.1771365PMC PMC13076347
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Abstract

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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Figure 1 Hypoxia-mediated metabolic reprogramming in cancer cells.This schematic illustrates how hypoxic conditions within the tumor microenvironment stabilize hypoxia-inducible factors (HIF-1α and HIF-2α), which act as central transcriptional regulators orchestrating widespread metabolic adaptations that promote tumor survival, growth, and immune evasion. Under hypoxia, HIF-1α drives a shift toward aerobic glycolysis by upregulating glucose transporters (GLUT1/3) and key glycolytic enzymes (HK2, LDHA), while induction of pyruvate dehydrogenase kinase-1 (PDK1) inhibits pyruvate entry into the tricarboxylic acid (TCA) cycle, thereby suppressing mitochondrial oxidative phosphorylation (OXPHOS). Excess pyruvate is converted to lactate, which is exported via monocarboxylate transporter-4 (MCT4), contributing to extracellular acidification, metabolic symbiosis, and immunosuppression. In parallel, hypoxia enhances glutamine metabolism, particularly through HIF-2α-dependent pathways, supporting anaplerosis, reductive carboxylation, and lipid biosynthesis. Lipid metabolic reprogramming is characterized by increased fatty acid uptake, de novo lipogenesis, and lipid droplet accumulation, which provide energy reserves and protect against oxidative stress. Increased flux through the pentose phosphate pathway (PPP) generates NADPH and nucleotides, maintaining redox homeostasis and supporting biosynthetic demands. Hypoxia also modulates amino acid metabolism, notably serine–glycine–one-carbon pathways, to sustain nucleotide synthesis and redox balance. Additionally, HIF-regulated iron and heme metabolism ensures iron availability for essential cellular processes.
Figure 1 Hypoxia-mediated metabolic reprogramming in cancer cells.This schematic illustrates how hypoxic conditions within the tumor microenvironment stabilize hypoxia-inducible factors (HIF-1α and HIF-2α), which act as central transcriptional regulators orchestrating widespread metabolic adaptations that promote tumor survival, growth, and immune evasion. Under hypoxia, HIF-1α drives a shift toward aerobic glycolysis by upregulating glucose transporters (GLUT1/3) and key glycolytic enzymes (HK2, LDHA), while induction of pyruvate dehydrogenase kinase-1 (PDK1) inhibits pyruvate entry into the tricarboxylic acid (TCA) cycle, thereby suppressing mitochondrial oxidative phosphorylation (OXPHOS). Excess pyruvate is converted to lactate, which is exported via monocarboxylate transporter-4 (MCT4), contributing to extracellular acidification, metabolic symbiosis, and immunosuppression. In parallel, hypoxia enhances glutamine metabolism, particularly through HIF-2α-dependent pathways, supporting anaplerosis, reductive carboxylation, and lipid biosynthesis. Lipid metabolic reprogramming is characterized by increased fatty acid uptake, de novo lipogenesis, and lipid droplet accumulation, which provide energy reserves and protect against oxidative stress. Increased flux through the pentose phosphate pathway (PPP) generates NADPH and nucleotides, maintaining redox homeostasis and supporting biosynthetic demands. Hypoxia also modulates amino acid metabolism, notably serine–glycine–one-carbon pathways, to sustain nucleotide synthesis and redox balance. Additionally, HIF-regulated iron and heme metabolism ensures iron availability for essential cellular processes.CC BY · PubMed Central
Figure 2 Metabolic reprogramming in the hypoxic tumor microenvironment drives cancer aggressiveness. Under normoxic conditions, tumor cells primarily depend on mitochondrial oxidative phosphorylation for ATP generation. In contrast, under low oxygen conditions, HIFs initiate a cascade of transcriptional changes that promote metabolic adaptation. Key features include a glycolytic shift (Warburg effect), characterized by increased glucose uptake, enhanced glycolysis, elevated lactate export and glutamine metabolism to support biosynthesis and reprogramming of lipid metabolism, to support membrane synthesis and energy needs. Additionally, suppression of mitochondrial oxidative metabolism contributes to redox homeostasis. [FASN: fatty acid synthase; CPT1A: carnitine palmitoyltransferase; PDK1: pyruvate dehydrogenase kinase 1; PK – Pyruvate Kinase; PFK – Phosphofructokinase; LDH – Lactate Dehydrogenase; LDH2 – Lactate Dehydrogenase Isoenzyme 2; MCT – Monocarboxylate Transporter.]
Figure 2 Metabolic reprogramming in the hypoxic tumor microenvironment drives cancer aggressiveness. Under normoxic conditions, tumor cells primarily depend on mitochondrial oxidative phosphorylation for ATP generation. In contrast, under low oxygen conditions, HIFs initiate a cascade of transcriptional changes that promote metabolic adaptation. Key features include a glycolytic shift (Warburg effect), characterized by increased glucose uptake, enhanced glycolysis, elevated lactate export and glutamine metabolism to support biosynthesis and reprogramming of lipid metabolism, to support membrane synthesis and energy needs. Additionally, suppression of mitochondrial oxidative metabolism contributes to redox homeostasis. [FASN: fatty acid synthase; CPT1A: carnitine palmitoyltransferase; PDK1: pyruvate dehydrogenase kinase 1; PK – Pyruvate Kinase; PFK – Phosphofructokinase; LDH – Lactate Dehydrogenase; LDH2 – Lactate Dehydrogenase Isoenzyme 2; MCT – Monocarboxylate Transporter.]CC BY · PubMed Central
Figure 3 Hypoxia-Induced Angiogenesis in the Tumor Microenvironment: Within the hypoxic tumor microenvironment, reduced oxygen availability stabilizes HIF-1α, which transcriptionally upregulates pro-angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF promotes the angiogenic cascade, which involves endothelial cell activation, degradation of the basement membrane, and the sprouting of new capillary vessels toward hypoxic regions. However, due to the uncoordinated and excessive nature of tumor angiogenesis, the newly formed vessels are tortuous, dilated, leaky, and poorly organized, resulting in inefficient perfusion and perpetuation of hypoxia.
Figure 3 Hypoxia-Induced Angiogenesis in the Tumor Microenvironment: Within the hypoxic tumor microenvironment, reduced oxygen availability stabilizes HIF-1α, which transcriptionally upregulates pro-angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF promotes the angiogenic cascade, which involves endothelial cell activation, degradation of the basement membrane, and the sprouting of new capillary vessels toward hypoxic regions. However, due to the uncoordinated and excessive nature of tumor angiogenesis, the newly formed vessels are tortuous, dilated, leaky, and poorly organized, resulting in inefficient perfusion and perpetuation of hypoxia.CC BY · PubMed Central
Figure 4 Regulation of HIF-1α by Oxygen Levels under Normoxic and Hypoxic Conditions. Under normoxic conditions (left panel), HIF-1α is hydroxylated by prolyl hydroxylase domain (PHD) enzymes in an oxygen-dependent manner. This hydroxylation targets HIF-1α for recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, leading to its ubiquitination and subsequent degradation by the proteasome, thereby maintaining low intracellular HIF-1α levels and preventing transcriptional activation. In contrast, under hypoxic conditions (right panel), PHD enzymes are inactivated due to the lack of oxygen, allowing HIF-1α to accumulate and translocate into the nucleus. There, it dimerizes with HIF-1β and binds to hypoxia-response elements (HREs) on DNA, recruiting co-activators such as CBP/p300 to initiate the transcription of hypoxia-responsive genes like VEGF and EPO, facilitating cellular adaptation to low oxygen.
Figure 4 Regulation of HIF-1α by Oxygen Levels under Normoxic and Hypoxic Conditions. Under normoxic conditions (left panel), HIF-1α is hydroxylated by prolyl hydroxylase domain (PHD) enzymes in an oxygen-dependent manner. This hydroxylation targets HIF-1α for recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, leading to its ubiquitination and subsequent degradation by the proteasome, thereby maintaining low intracellular HIF-1α levels and preventing transcriptional activation. In contrast, under hypoxic conditions (right panel), PHD enzymes are inactivated due to the lack of oxygen, allowing HIF-1α to accumulate and translocate into the nucleus. There, it dimerizes with HIF-1β and binds to hypoxia-response elements (HREs) on DNA, recruiting co-activators such as CBP/p300 to initiate the transcription of hypoxia-responsive genes like VEGF and EPO, facilitating cellular adaptation to low oxygen.CC BY · PubMed Central
Figure 5 Mechanism of HIF-1 in Hypoxic Tumors. In the hypoxic tumor microenvironment, oxygen deprivation stabilizes hypoxia-inducible factors (HIF-1α, HIF-2α, and HIF-3α) and their constitutively expressed partner HIF-1β. The active HIF complexes translocate to the nucleus and induce the transcription of a wide array of target genes that promote tumor progression. These include genes regulating cancer cell proliferation and survival (e.g., IGF2, Cyclin D1), epithelial–mesenchymal transition and metastasis (e.g., CXCR4, MMPs), metabolic reprogramming (e.g., GLUT1, LDHA, HK2), angiogenesis (e.g., VEGF, PDGF), and immunosuppression (e.g., PD-L1).
Figure 5 Mechanism of HIF-1 in Hypoxic Tumors. In the hypoxic tumor microenvironment, oxygen deprivation stabilizes hypoxia-inducible factors (HIF-1α, HIF-2α, and HIF-3α) and their constitutively expressed partner HIF-1β. The active HIF complexes translocate to the nucleus and induce the transcription of a wide array of target genes that promote tumor progression. These include genes regulating cancer cell proliferation and survival (e.g., IGF2, Cyclin D1), epithelial–mesenchymal transition and metastasis (e.g., CXCR4, MMPs), metabolic reprogramming (e.g., GLUT1, LDHA, HK2), angiogenesis (e.g., VEGF, PDGF), and immunosuppression (e.g., PD-L1).CC BY · PubMed Central
Figure 6 Implications of Metabolic Reprogramming in the Tumor Microenvironment. The central hypoxic tumor cell undergoes metabolic reprogramming characterised by increased glycolysis, elevated lactate production, and reduced oxidative phosphorylation (OXPHOS). These metabolic alterations lead to the accumulation of acidic metabolites and promote survival under oxygen-deprived conditions. Increased glycolysis supports cancer cell survival and proliferation in hypoxic niches by generating ATP anaerobically and producing lactate. The extracellular accumulation of lactate and resulting acidification promote extracellular matrix degradation and epithelial-to-mesenchymal transition (EMT), aiding invasion and metastasis. The acidic and lactate-rich microenvironment also suppresses cytotoxic T cells and NK cells, impairs dendritic cell function, and favors the recruitment of immunosuppressive regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), promoting immune evasion. Persistent hypoxia and metabolic stress drive therapy resistance through adaptive genetic and epigenetic modifications, enhancing tumor cell plasticity and promoting survival against anticancer treatments.
Figure 6 Implications of Metabolic Reprogramming in the Tumor Microenvironment. The central hypoxic tumor cell undergoes metabolic reprogramming characterised by increased glycolysis, elevated lactate production, and reduced oxidative phosphorylation (OXPHOS). These metabolic alterations lead to the accumulation of acidic metabolites and promote survival under oxygen-deprived conditions. Increased glycolysis supports cancer cell survival and proliferation in hypoxic niches by generating ATP anaerobically and producing lactate. The extracellular accumulation of lactate and resulting acidification promote extracellular matrix degradation and epithelial-to-mesenchymal transition (EMT), aiding invasion and metastasis. The acidic and lactate-rich microenvironment also suppresses cytotoxic T cells and NK cells, impairs dendritic cell function, and favors the recruitment of immunosuppressive regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), promoting immune evasion. Persistent hypoxia and metabolic stress drive therapy resistance through adaptive genetic and epigenetic modifications, enhancing tumor cell plasticity and promoting survival against anticancer treatments.CC BY · PubMed Central

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Research works printed but not linked: 8

  1. Calorini, 2012, Extracellular acidity as favouring factor of tumor progression and metastatic dissemination, Exp Oncol, 34, 79
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  3. Jarc, 2019, Lipid droplets and the management of cellular stress, Yale J Biol Med, 92
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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)
DOI
10.3389/fonc.2026.1771365
PMC
PMC13076347
OpenAlex
W7143706570
Cited by
11
References
313
Citations by year
2026: 11
FWCI
9.23
Type
journal article
Language
en
Open access
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

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