Role of hyperoxic treatment in cancer

Abstract

The occurrence of hypoxia is common in many solid tumors, and it enhances aggressive features of cancer such as cell survival, angiogenesis, and metastasis while minimizing the efficacies of chemotherapy and radiotherapy. Hypoxia also plays a pivotal role in regulating immune cell function which is important for immunotherapy. Hypoxia-inducible factor has been suggested as a master regulator of tumor cell adaptation to the hypoxic microenvironment. Currently, several approaches have been proposed to eliminate the hypoxic state in tumors for delaying cancer progression and improving therapeutic efficacy. In this review, we summarize current findings on the relevance of hyperoxia-based therapeutics for cancer treatment. Accumulating evidence indicates that hyperoxic therapy inhibits tumor growth and increases treatment efficacy. Primary antitumor effect of hyperoxic therapy may be due to the reversal of tumor hypoxia and the generation of reactive oxygen species. Restoring immune function is also suggested as a potential mechanism. Hyperoxic therapy can also cause cellular injury and organ dysfunction. In conclusion, overcoming tumor hypoxia is a major problem that needs to be solved. Further studies to standardize and personalize hyperoxia therapy according to the type of cancer, stage, and comorbidities are needed.

Impact statement

Tumor hypoxia promotes cancer cell aggressiveness, and is strongly associated with poor prognosis across multiple tumor types. The hypoxic microenvironments inside tumors also limit the effectiveness of radiotherapy, chemotherapy, and immunotherapy. Several approaches to eliminate hypoxic state in tumors have been proposed to delay cancer progression and improve therapeutic efficacies. This review will summarize current knowledge on hyperoxia, used alone or in combination with other therapeutic modalities, in cancer treatment. Molecular mechanisms and undesired side effects of hyperoxia will also be discussed.

Introduction

Oxygen is an indispensable element for cells in our body to fulfill energy requirement from aerobic metabolism. Therefore, reduced oxygen levels, hypoxia, may produce cell death and resulting organ dysfunction as occurs in heart attacks or strokes. Hypoxia commonly arises in the core of most solid tumors as a result of an inadequate supply of oxygen from abnormal vasculature, and an increased oxygen demand from changes in tumor metabolism.¹Severity of tumor hypoxia varies depending on tissue of origin and tumor size, and median oxygen levels in untreated tumors are frequently less than 2% in comparison to the normal human tissues (5%).^2,3The hypoxic regions within the tumor are heterogeneously distributed and may even located near to vessels.⁴

Traditionally, hypoxia was thought of as a factor limiting the cancer growth by reducing the ability of cells to divide.⁵However, increasing evidence indicates that tumor hypoxia plays an important role in cancer progression. When tumor cells adapt to the imbalance between oxygen supply and demand, malignant features of solid tumors such as resistance to cell death, angiogenesis, and metastasis were invariably enhanced.^6,7Emerging features of cancer development such as genome instability, the enrichment of cancer stem cells, and aberrant exosomal secretion were also suggested as hallmarks of tumor hypoxia.^8–10Overall, hypoxic microenvironment in tumor promotes acquisition of the more aggressive cancer phenotypes and thus is associated with poor prognosis.^11,12In addition, tumor hypoxia has been considered as one of the biggest barriers to treating cancer because it renders tumors more resistant to surgery, radiotherapy, chemotherapy, and immunotherapy.^13–16In this regard, it is widely accepted that hypoxia is a potential cancer-specific target,^11,17and several approaches targeting tumor hypoxia for cancer therapy such as erythropoietin, nicotinamide, hypoxia-activated prodrugs, and nanocarriers have been proposed.^14,18

Numerous studies also suggest increasing oxygen content using hyperoxia as a promising therapeutic modality to reverse tumor hypoxia as well as resistance to cancer therapeutics.^5,19–21Recently, we also identified anti-cancer effect of hyperoxia and its mechanism of action in mouse lung cancer.^22,23However, despite of growing interest and clinical trials, the application of hyperoxia to cancer treatment is still in its nascent stage. Here, we will focus on the recent insights into the understanding of hyperoxia-mediated cancer treatment.

Hyperoxic therapy in cancer

Oxygen therapy is a type of treatment to enhance the amount of dissolved oxygen in the plasma by breathing supplemental oxygen, thereby increasing O₂delivery to body tissue. For hyperoxygenation, 100% oxygen is administered to a patient either at ambient atmospheric pressure (normobaric oxygen, NBO) or under hyperbaric conditions usually in a pressurized chamber (hyperbaric oxygen, HBO). Oxygen therapy has long been regarded as integral to the management of various medical conditions for centuries. For cancer treatment, there is still no evidence that it is effective in treating cancer.²⁴However, despite ongoing controversy, interest in applying hyperoxic therapy as adjuvant for cancer treatment is rapidly growing. For example, in Pubmed search concerning oxygen therapy and cancer, since the first article in 1951,²⁵more than 20,000 were found. A brief summary of hyperoxic therapies on cancer is listed in Table 1.

Table 1.

Summary of studies on cancer with hyperoxic therapies.

References	Year	Type of tumor	Type of hyperpoxic treatment	Combination treatment	Summary of the study
Moen et al.26	2009	DMBA-induced mammary tumor mouse model	2 bar, pO2 = 2 bar, 4 times (day 1, 4, 7 and 10) exposures of 90 min	5-FU	HBO increases the uptake of [3H]-5FU
Kawasoe et al.27	2009	Osteosarcoma LM8 cells mouse model	2.5 bar, pO2 = 2.5 bar, 60 min, 5 times a week until 5 weeks	Carboplatin	HBO or HBO with carboplatin inhibits tumor growth and lung metastasis, synergistically
Selvendiran et al.28	2010	A2780 ovarian xenograft tumor mouse model	100% O22 atm for 90 min, 21 days	Cisplatin	Reduction of tumor volume. No significance between HBO and cisplatin-treated group
Sun et al.29	2012	Human glioblastoma multiforme cells (D54, U87)	40%, 80% O2, 72 h	Temozolomide	NBO enhanced TMZ toxicity in GBM cells
Lee et al.30	2014	Human glioblastoma multiforme cells (D54, U87, U251)	40% O2, 24, 48 and 72 h	Temozolomide	NBO enhanced the sensitivity to temozolomide in chemosensitive and -resistant GBM cells
Hatfield et al.31	2016	MCA205 fibrosarcoma mouse model	60% O2, 72 h and 11 days	–	NBO reverses the hypoxia–A2-adenosinergic immunosuppression during acute inflammation
Yttersian Sletta et al.21	2017	Breast cancer mouse model	2.5 bar, pO2 = 2.5 bar, 90 min, every third day until day 16	5-FU	Suppressed tumor growth and metastatic lesions, HBO does not enhance the 5-FU efficacy
Kim et al.23	2018	Lewis lung carcinoma cell injected mouse model	24 h NBO (95% O2)/normoxia cycle for two weeks	–	NBO inhibits the progression of lung cancer by inducing apoptosis
Lee et al.22	2018	benzo[a]pyrene -induced lung tumorigenesis mouse model	95% O2for 3 h/day, days 21–28	Carboplatin	Intermittent NBO with carboplatin displays a synergistic tumoricidal effect
Qian et al.20	2019	triple-negative breast cancer mouse model	60% O2, day 7-28	–	NBO reverses immunosuppression and control the extend of lung metastases

In addition to oxygen breathing, although relatively uncommon, other forms of oxygen therapy such as oxygen-containing substances (i.e. ozone or hydrogen peroxide), and prodrugs that are activated only in the hypoxic tumor environment also have been tried for cancer treatment.^32–34

Hyperbaric oxygen therapy

HBO treatment is breathing 100% oxygen at higher atmospheric pressure usually between 1.5 and 3 atm which enable the lungs to receive more oxygen up to three times than under normal air pressure, resulting in immediate saturation of plasma with oxygen. In normal subject, compared to normobaric air, HBO at 3 atm increases both arterial (from 100 to 2000 mmHg) and tissue (from 55 to 500 mmHg) oxygen tensions (PO₂).³⁵Similarly, the PO₂level was significantly increased in tumor tissue by HBO exposure, demonstrating three to four times greater hyperoxygenation effect in tumor tissue than NBO.^36,37Therefore, HBO rather than NBO has been preferentially used to eliminate poorly oxygenated regions of tumor which play a major role in tumor development and resistance to other therapeutic modalities. In addition, HBO therapy is considered safe and well tolerated, and side effects are rare.³⁸Although several studies showed the favorable outcomes of HBO by itself in cancer treatment,^5,28,39HBO alone gives a limited curative effects, and it even enhances tumor growth.^19,40Accordingly, HBO is preferentially used as an adjuvant treatment for enhancing tumor sensitivity and decreasing complications of other therapies.³⁴

Normobaric oxygen therapy

NBO therapy is a routine adjuvant oxygenation intervention supplied by nasal cannula or facemask under ambient pressure. For cancer treatment, NBO is an attractive alternative to HBO due to its ease of administration and lower complication in actual clinical practice.⁴¹However, when compared to HBO, effect of NBO on arterial and tissue oxygenation is much weaker. Arterial PO₂in aorta has increased only 4-fold after exposure to NBO (345 vs. 84.1 mmHg).⁴²In animal study, most of tumors were nearly anoxic (PO₂<1 mmHg), but NBO immediately increased PO₂(mean >25 mmHg) and remained elevated during gas exposure.⁴³Accordingly, NBO treatment significantly retarded tumor growth.^39,44We also previously showed the NBO inhibits lung cancer in in vivoand in vitrothrough reactive oxygen species (ROS) generation and apoptosis.²³

Molecular mechanisms: Hypoxia-inducible factor 1α

Hypoxia

When oxygen levels in tumor microenvironment are dropping, transcriptional induction of a series of genes necessary for maintaining cell survival/proliferation and promoting more aggressive features occurs in tumor cells. These oxygen-dependent responses are tightly regulated by HIF-1α, the master transcriptional regulator of the hypoxic response as well as a representative endogenous biomarker for hypoxia.⁴⁵HIF-1α is induced by hypoxia through post-translational modification, and it binds to specific recognition sequences in the genome to increase the expression of HIF-1α target genes.⁴⁶Since the seminal discovery of HIF in the early 1990s by Gregg Semenza, a Nobel Laureate in Physiology or Medicine for 2019,⁴⁷thousands of genes are identified as direct targets of HIF-1α,⁴⁸and therefore a myriad of changes associated with tumor aggravation occur in hypoxic tumor cells including angiogenesis and oxygen supply, stemness/self-renewal, proliferation, epithelial to mesenchymal transition, metastasis and invasion, redox homoestasis, anti-apoptosis, and metabolic reprogramming.^49,50Metabolic reprogramming from oxidative phosphorylation to accelerated glycolysis in cancer cells is also known to be mediated via HIF-1α.⁵¹In addition, HIF-1α contributes to the development of tumor resistance to therapeutic approaches and serves as a promising biomarker.^52,53For example, HIF-1α limits T cell recognition of tumor cells by downregulating MHC class I molecule expression.⁵⁴It also induces multidrug resistance, the major cause of chemotherapy failure, by inducing multidrug resistance-associated protein 1 in cancer cells.⁵⁵Accordingly, in cancer patients, protein levels of HIF-1α in solid tumors are considered as a critical prognostic factor.⁵⁶Based on these findings, HIF-1α has become targets for developing novel cancer therapeutics. However, no agents directly inhibiting HIF-1α have been approved for treating cancer patients.⁵⁷

Hyperoxia

Many reports suggest various beneficial effects of hyperoxia on hypoxic tumor. Hyperoxic breathing of 60% O₂recovers oxygen homeostasis in tumor microenvironment hypoxia to normoxia, inhibits survival/proliferation, stemness, and immune escape of cancer cells, resensitizes chemoresistance, leading to tumor regression.^29,58,59We also reported anti-cancer effects of hyperoxia, alone or in combination with a chemotherapeutic drug carboplatin, on mouse lung cancer; normobaric hyperoxia significantly induces oxidative stress and apoptosis in tumor tissue and reduces tumor mass and migration/invasion.^22,23Differential response of cancer and normal cells to hyperoxia has also provided a treatment rationale of hyperoxia in cancer treatment. Basal antioxidant defense levels are aberrant in tumor cells, thus an increased oxidative stress has been observed. Since the superoxide dismutase activity in most tumors are lower than normal tissue, tumor cells show higher susceptibility to increased ROS activity induced by hyperoxia.⁶⁰Synthesis of glutathione (GSH), an antioxidant preventing ROS-induced damage, increases proportional to ambient oxygen tension, but not in cancer cells.⁶¹In consistent with these findings, we demonstrated that NBO showed anti-tumor activity in lung tumor cells but not in normal lung cells.²³In addition, hyperoxia is angiogenic in normal tissues, but anti-angiogenic in tumor tissues.⁶²

Anti-cancer mechanisms of hyperoxia can also be inferred indirectly from clinical and experimental findings. Roles of HIF-1α in hypoxia-mediated cancer development are widely acknowledged, and hyperoxic treatment has long been used to cure clinical disorders such as hypoxia or ischemic diseases by increasing oxygen delivery to oxygen-deficient tissues. We can also take a hint from well-known mechanisms for the induction and regulation of HIF-1α: HIF-1α protein is subject to degradation through an oxygen-dependent ubiquitination,⁶³and hypoxia-induced HIF-1α protein is rapidly decayed within 5 min upon exposure to normoxia (20% O₂).⁶⁴In addition, transcriptional activity of HIF-1α is enhanced by hypoxia-induced ROS,⁶⁵and inhibited by oxygen in nonhypoxic cells.⁶⁶Taken these findings together, it seems reasonable that therapeutic effects of hyperoxia on hypoxic tumor are mediated through not direct regulation of HIF-1α but primarily the reversal of hypoxia and the attenuation of the HIF-mediated effects.

However, despite of accumulating evidence supporting this idea, many reports also indicate HIF-1α–independent effects of hyperoxia on tumor. For example, both normoxia and hyperoxia induces higher levels of HIF-1α than hypoxia in tumors, but tumor grows faster in hypoxia group, suggesting that signaling pathways other than HIF-1α driven response may play important roles for in vivocancer cell proliferation.⁶⁷Recent report also showed that HIF-1α levels in tumor cells was significantly downregulated in hyperoxia (60% O₂) than normoxia (20% O₂), indicating that alternative mechanisms other than simple reversal of tumor hypoxia to normoxia underlie anti-tumor effects of hyperoxia.⁵⁹Coincidentally, Rocco et al.⁶⁸suggest that relative changes of oxygen availability rather than steady state hypoxic or hyperoxic conditions play an important role in HIF transcriptional effects. In addition, hyperoxia activates HIF-1α overexpression through the activation of Src oncogene, and also inhibits the stability of HIF-1α by reducing ROS formation.^65,69,70Despite numerous attempts, mechanisms underlying hyperoxia-mediated anti-cancer activity remain to be elucidated.

Side effects

Hyperoxic therapy is usually well tolerated with an acceptable rate of complications; however, as with all medical treatments, it also includes medical risks. Dependent on the type of hyperoxic therapy, patients may experience two prominent side effects due to exposure to high levels of oxygen (oxygen toxicity) or high atmospheric pressure (barotrauma). As shown above, PO₂used in HBO therapy is much higher than that of NBO, thus oxygen toxicity is more common in patients exposed to HBO. In addition, only HBO therapy is carried out in a hyperbaric chamber, thus barotrauma occurs only in patients taking HBO therapy.

Oxygen toxicity

Exposure to high concentration of oxygen is well known cause of cell damage. For example, oxygen, at concentrations of 95% or more, is severely cytotoxic to the pulmonary cells of many animal species, including humans.⁷¹Humans appear more resistant to oxygen-induced damage and the risk of hyperoxic acute lung injury is minimal when the FiO2 is $\text{≤}$0.6⁷²but continuous exposure to elevated levels of oxygen may cause oxygen toxicity. Major organs subject to oxygen toxicity are lungs (hyperoxic acute lung injury), central nervous system (loss of consciousness and oxygen toxicity seizure), and eye (hyperoxic myopia and cataract).^73–75Oxygen toxicity is believed to be mediated primarily by a production of ROS at levels exceeding the capacity of antioxidant defence mechanisms.⁷⁶Following HBO treatment, ROS increased to about 2.14–2.44 fold in mitochondria and 1.32–1.42 fold in whole cell.⁷⁷Reduction of antioxidant enzymes such as superoxide dismutase and glutathione by HBO, but not by NBO, also contributes to increased oxygen toxicity.⁷⁸Excessive ROS can damage all essential macromolecules, including nucleic acids, lipids and proteins, leading to an overall progressive decline in physiological function.⁷⁹For example, protein oxidation and nitrosylation can impair a wide variety of enzymatic processes and growth factors that can result in marked cellular dysfunction.⁸⁰Lipid peroxidation activates apoptosis through activation of sphingomyelinase and release of ceramide.⁸¹Nucleic acid oxidation has been linked with aging and DNA strand breaks, leading to necrosis and/or apoptosis.⁸²Therefore, HBO-driven ROS can display many harmful activities including the induction of DNA damage, cell death, cellular senescence, and deleterious inflammatory response which in turn exacerbates oxidative toxicity and tissue damage.^83,84Several mechanisms involved in hyperoxia-induced oxygen toxicity have been proposed. For example, ROS stimulates signaling pathways mediated via protein kinases (Akt, MAPK and PKC), resulting in activation of transcription factors (Nrf2, NF-κB, and AP-1) responsible for cell death and inflammation.⁸⁵In addition, ROS-independent mechanisms such as the induction of apoptosis by direct activation of Bax, Bak, or FAS,⁸⁶chemokine receptor CXCR2-mediated tissue inflammation,⁸⁷and toll-like receptor-linked cell damages⁸⁸also have been suggested.

Barotrauma and other complications

In HBO therapy, unlike to NBO, patients are exposed to the high atmospheric pressure in hyperbaric chamber. Barotrauma, pressure-induced injury, is caused by inability to equalize pressure between the environment and the air-filled space in the body such as lungs, ear, sinuses, eyes, and teeth are concurrently at risk. The most common type of barotrauma (>17%) is middle ear barotrauma which can lead to permanent hearing loss and vertigo.⁸⁹

Some patients can develop a feeling of claustrophobia, the fear of being enclosed in small spaces with no escape, due to the confined nature of hyperbaric chamber. HBO therapy also causes mild increase in blood pressure in both hypertensive and non-hypertensive patients, and hypoglycemia can occur in diabetic patients.⁹⁰In addition, NBO increases pulmonary metastasis of tumor⁹¹and inhibits glucose-induced insulin release.⁹²

Because hyperoxia, unlike hypoxia, is a man-made condition, specific adaptive response to hyperoxia has not been evolved in humans. To enhance safety and to prevent side-effects of HBO therapy in cancer treatment as well as other clinical trials, further investigation to maximize therapeutic efficacy and minimize complications by standardizing therapy protocol in particular with regard to pressure and duration is required.

Role of hyperoxia treatment in chemotherapy

Hypoxia reduces the sensitivity of cancer to chemotherapy.⁶In addition, hypoxic cells do not receive sufficient chemotherapeutic agents due to distance from the capillary and because of abnormal vascularization of tumors. Hypoxia remotes resistance through the HIF-1-mediated upregulation of different genes and signaling pathways.⁹³Hypoxia-induced drug resistance is also explained by inhibition of apoptotic pathways^23,94and increased intracellular drug efflux.⁹⁵Currently, respiratory hyperoxia is mainly used for the treatment of hypoxic tissue damage. Also, hyperoxia has also been shown to improve the treatment efficacy of chemotherapy in animal models.^20,22,26From our previous study, NBO therapy was found to be tumoricidal and NBO with carboplatin exhibited a synergistic antitumor effect on B[a]P-induced lung cancers in mice.^22,23Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors. Lee et al.³⁰showed that NBO treatment resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response.

Other studies were mostly performed under HBO treatment. Moen et al.²⁶showed that HBO treatment increases the uptake of 5-fluorouracil in mammary tumors for the duration of, and immediately after, HBO treatment. Kawasoe et al.²⁷showed significant suppression of osteosarcoma with HBO plus carboplatin compared with monotherapy, both in in vitroand in vivo.Other studies also showed increased efficacy against variety of malignancies with combination of HBO and chemotherapy.^28,96,97However, precise mechanisms are not known until now and more standard combination treatment protocols are needed. In addition, a combination of HBO treatment and particular chemotherapeutic agents (doxorubicin, bleomycin, and disulfiram) may cause potential toxicity⁹⁸because it can potentiate oxygen-related serious organ damage.^99–101However, studies showing conflicting results also exist.^102,103

Role of hyperoxic treatment in radiation therapy

The primary mechanism of radiation therapy is creation of ROS, which in turn induces cell death by the mechanisms including apoptosis, necrosis, autophagy, and senescence.¹⁰⁴In hypoxic state, DNA radicals are repaired by abstracting hydrogen from sulfhydryl group present in protein.¹Since oxygen is required for ROS generation, hypoxic tumors are resistant to the cytotoxic effects of radiotherapy.¹⁰⁵HIF-1 plays a role in radioresistance of a tumor by up-regulating downstream genes, which are involved in apoptosis, metabolism, proliferation, and neovascularization.¹⁰⁶In general, cells irradiated under normal oxygenated conditions are two- to three-fold more radiosensitive than cells irradiated under hypoxic or anoxic conditions.^107,108Several human studies reported significant improvement of survival and local tumor control in patients with cancer treated with radiotherapy and HBO.^109–111However, other studies suggest a high rate of complications from combination of HBO and radiotherapy, including severe tissue radiation injury and seizures.^34,110Concerning this matter, beneficial effects of NBO on tumor radiosensitivity have been also reported.^112,113In addition, both the extent and the timing of this hyperoxic therapy are variable. From systematic reviews in patients with high grade gliomas, radiation therapy after HBO treatment was tolerated and beneficial.¹¹¹

Role of hyperoxic treatment in immunotherapy

Oxygen tension directly affects immune cell function, and thus hypoxia can cause immunosuppression and/or immune dysfunction.¹¹⁴It is widely appreciated that hypoxic tumor microenvironment negatively affects anti-tumor immune responses, and also is responsible for resistance to immunotherapy.^16,115Many mechanisms underlying hypoxia-induced immunomodulation in cancer have been suggested.¹¹⁶Extracellular adenosine, a potent immunosuppressive metabolite, is increased in hypoxic conditions, and controlled by two cell surface nucleotidases; CD39 and CD73 in tumors,^117,118providing evidence that the adenosine-dependent immunoregulation is important for hypoxia-mediated immunosuppression. TGF-β, a potent immunosuppressive cytokine, is upregulated in tumor cells after culturing in hypoxic conditions.¹¹⁹Hypoxia also increases the accumulation of intracellular adenosine by HIF-1α-dependent mechanism, resulting in the elevation of extracellular adenosine independent of CD39/CD73.^120,121Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1), important players in immune checkpoint pathways, are also regulated oxygen-dependently in the tumor microenvironment. Hypoxia increases PD-L1 expression which induces cancer cell resistance to T-cell dependent cytotoxicity.^122,123Exposure to adenosine or the activation of its receptors in T cells also downregulates T cell activities by inducing PD-1 and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression.^124,125Activities of myeloid-derived suppressor cells (MDSCs), typical immunosuppressive cells in the tumor microenvironment, are also regulated by hypoxia and extracellular adenosine.^126,127

Based on these findings, hyperoxia therapy has been attempted to restore hypoxia-induced impairment of immune function in cancer cells, in particular by downregulation of immune checkpoint pathways.³¹In mice, 60% oxygen efficiently reduced tumor burden only in wild-type mice, but not in immunocompromised mice, indicating the involvement of immune response in anti-tumor activities of hyperoxia.³¹Hyperoxia-induced alleviation of hypoxia reduces the levels of immunosuppressive molecules such as adenosine, TGF-β and PD-L1 in the tumor, and enhances anti-tumor immune responses.^31,58,59Population of typical immunosuppressive immune cells such as MDSCs and Treg cells in the tumor microenvironment is also decreased by hyperoxia therapy.^20,31Recently, Wang et al.⁵⁹reported that hyperoxia reduces stemness of colorectal cancer cells through the inhibition of hypoxia-mediated production of exosome from granulocytic MDSCs.

The role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments. Accumulating evidence indicates that attenuation of immunosuppressive activity in the tumor microenvironment by regulating immune checkpoints is the key factor for the success of cancer immunotherapy.¹²⁸In this regard, it is intriguing that the inhibition of immune checkpoints pathways is the main mechanism underlying anti-tumor activity of hyperoxia.¹¹⁴Although several immune regulators and molecular mechanisms involved in hyperoxia-mediated antitumor activities have been identified, precise adjunctive role for hyperoxia in cancer immunotherapy still remains unclear.

Future directions and conclusion

Tumor hypoxia is a major treatment target for effective cancer therapy and inhibition of cancer progression. Hyperoxia therapy has been suggested to reverse cancer hypoxia, and it is more often used as an adjunctive treatment for cancer treatment along with other therapeutic modalities. Currently, no standard protocols for hyperoxic tumor therapy are approved. In case of combining hyperoxia with radiation, hyperoxic periods are relatively short and may not have significant side effects,³⁴but in other cases where oxygen is administered over a long period, hyperoxia can cause cellular injury and organ dysfunction. Further, randomized, large, and well-organized clinical research could reinforce the use of hyperoxia therapy in the clinical setting for cancer treatment with minimal complications. Furthermore, more personalized approach according to the type of cancer and comorbidities are needed. Hypoxia-activated prodrugs or HIF inhibitors are suggested as possible alternatives to hyperoxic cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments via hypoxia-activated prodrugs is increasing.¹²⁹In addition, combinations of clinical immunotherapy and immunomodulation from HIF inhibitor have a possibility of being powerful treatment option.¹³⁰In conclusion, overcoming tumor hypoxia is an urgent problem to be solved for effective treatment of cancer patients. Further research is required to determine the mechanism for the role of oxygen tension in cancer progress and treatment, and to develop standard protocols for increasing efficacies and safety of hyperoxia therapy in cancer.

Authors’ contributions

All authors contributed to the preparation of this manuscript and approved the final version. SWK and IKK wrote the manuscript. SHL reviewed and edited the manuscript.

DECLARATION OF CONFLICTING INTERESTS

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

FUNDING

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2058026) and by grants Clinical Research Laboratory of The Catholic University of Korea, St. Paul’s Hospital.

ORCID iD

Sei W Kim https://orcid.org/0000-0002-2798-421X