Hypoxia signaling in cancer: Implications for therapeutic interventions

Abstract

Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia-targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.

Keywords: hyperoxia; hypoxia‐inducible factor (HIF); immunotherapy; targeted theraphy; tumor hypoxia.

FIGURE 1

In the hypoxic tumor microenvironment, hypoxia‐inducible factor (HIF)‐1α is activated by a variety of receptors (such as TCR, GFR, IL‐6R, and TLR) on the plasma membrane through the mammalian target of rapamycin (mTOR), NF‐κB and JAK‐STAT signaling pathways. The accumulated HIF‐1α combines with HIF‐1β to form a dimer in the nucleus. CBP/P300 is a transcription cofactor, thus forming the HIF complex that initiates the transcriptional activity. The promotion of the transcription of multiple genes, such as vascular endothelial growth factor (VEGF), erythropoietin (EPO), and STAT3, is involved in cell adaptation to hypoxic stress. At the same time, HIF is degraded by proline hydroxylase (PHD), which is recognized by the ubiquitin ligase Von Hippel‒Lindau (VHL) for ubiquitination. Factors that inhibit HIF (FIH) can also suppress HIF‐1 expression by inhibiting its transcriptional activity

FIGURE 2

Schematic diagram of methods to improve tumor oxygenation. Tumor oxygenation improvement methods include the uptake of high‐concentration oxygen (normobaric/hyperbaric) or carbogen to increase vascular oxygen concentration, thereby increasing tumor oxygen partial pressure to reverse tumor hypoxia. Hemoglobin is an oxygen carrier that releases oxygen in tumor hypoxic tissue, and hyperthermia is used to increase blood flow by expanding blood vessels and leads to increases in oxygenation of the tumor. Antiangiogenic drugs normalize the overall function of tumor vessels to improve tumor blood supply and increase the tissue oxygen content. Drugs inhibit cellular respiration by inhibiting the oxidative respiratory chain, reducing the rate of oxygen consumption, and indirectly improving tumor oxygenation. Nanoparticles carry oxygen or catalyze the decomposition of H₂O₂ to obtain oxygen to relieve hypoxia in tumor tissue

FIGURE 3

A timeline of respiratory hyperoxia discoveries and research history, highlighting key findings

FIGURE 4

Antitumor effect of hyperoxia. Respiratory hyperoxia can through the following mechanisms. (A) Hyperoxia downregulates the concentration of glutathione in tumor cells, leading to intracellular oxidation‐reduction imbalance, excessive reactive oxygen species (ROS) production, and cell damage. (B) Hyperoxia promotes the increase of apoptosis‐related proteins Bax and Caspase 8, breaking mitochondria, and cell death. (C) The strong decrease in tumor cell proliferation under hyperoxia is associated with a marked inhibition of cell cycle progression, which is mainly characterized by the arrest in the G1, G2, and S phases. This G1/S phase arrest is associated with severe inhibition of cyclin‐dependent kinase 2 (CDK2) activity and DNA synthesis, and cell cycle progression from G1 to S is also inhibited. At the same time, hyperoxia induces cell arrest in the G2 phase by preventing the dimerization of cyclin B and the CDK1 complex and promotes cell apoptosis

FIGURE 5

Schematic diagram of the antitumor effect of hyperoxia‐assisted radiation therapy. Radiation ionizes the tumor tissue water to generate electrons (e^–), which need to be combined with oxygen (O₂) to generate oxygen free radicals (O2^.−). These radicals are oxidized by superoxide dismutase (SOD) to produce reactive oxygen species (H₂O₂). Hyperoxia promotes the antitumor effect of chemotherapy

FIGURE 6

Hyperoxia reverses the hypoxic tumor microenvironment and promotes antitumor immunity. (A) Supplemental oxygen reduces the strength of downstream adenosine 2a (A2a)‐mediated tumor microenvironment (TME) immunosuppression by attenuating upstream tumor hypoxia. This in turn unleashes the antitumor activity of the otherwise suppressed T cells and natural killer (NK) cells, causing the tumor to regress

FIGURE 7

Hyperoxia promotes the expression of MCH‐1 and inhibits the expression of PDL‐1. PD‐1 binds to PD‐L1, which can transmit inhibitory signals and reduce the production of T lymphocytes. Hypoxia‐inducible factor (HIF) inhibits the in vivo immune effect by reducing MHC‐1 and increasing PD‐L1 expression in tumor cells. Hyperoxia has an antitumor effect by reversing tumor hypoxia and reducing PD‐L1 expression and can be applied in combination with an anti‐PD‐L1 antibody. Hyperoxia also promoted the upregulation of NOX₂ in neutrophils, resulting in the increase of reactive oxygen species (ROS) and increased killing of tumor cells. Myeloid‐derived suppressor cells (MDSCs) can produce exosomes (mainly including S100A9) that promote the proliferation of tumor cells, and hyperoxia can reduce the production of exosomes by MDSCs and inhibit the proliferation of tumors