Implications of Hyperoxia over the Tumor Microenvironment: An Overview Highlighting the Importance of the Immune System

Abstract

Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in the toxicity of the therapeutic agent improves the efficacy of therapies such as chemotherapy. Radiotherapy efficacy has also improved, where apoptotic mechanisms seem to be implicated. Moreover, hyperoxia increases the antitumor immunity through diverse pathways, leading to an immunopermissive TME. Although hyperoxia is an approved treatment for preventing and treating hypoxemia, it has harmful side-effects. Prolonged exposure to high oxygen levels may cause acute lung injury, characterized by an exacerbated immune response, and the destruction of the alveolar–capillary barrier. Furthermore, under this situation, the high concentration of ROS may cause toxicity that will lead not only to cell death but also to an increase in chemoattractant and proinflammatory cytokine secretion. This would end in a lung leukocyte recruitment and, therefore, lung damage. Moreover, unregulated inflammation causes different consequences promoting tumor development and metastasis. This process is known as protumor inflammation, where different cell types and molecules are implicated; for instance, IL-1β has been described as a key cytokine. Although current results show benefits over cancer therapies using hyperoxia, further studies need to be conducted, not only to improve tumor regression, but also to prevent its collateral damage.

A single-cell transcriptome analysis and prognostic model construction of stromal cells for renal cell carcinoma

“…5D ), further confirming the role of hypoxia in RCC tumor cells. An improvement in the immune response related to phagocytosis and leukocyte activation has also been observed, which is consistent with previous findings in many solid tumors (Herrera-Campos et al 2022; Terrén et al 2019). The change in the prominent position from hypoxia- and oxygen-sensing pathways in scRNA-seq to immune response-related pathways in bulk RNA was mainly due to the differences in the analyzed objects.…”

Hypoxia signaling in cancer: Implications for therapeutic interventions

“…Furthermore, HBO disrupts hypoxia‐mediated immunosuppression and helps PD‐1 Ab trigger robust cytotoxic T lymphocyte responses and durable immune memory to suppress tumor recurrence. 423 , 424 …”

“…Furthermore, HBO disrupts hypoxiamediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocyte responses and durable immune memory to suppress tumor recurrence. 423,424 Research has shown that an important component of hyperoxia therapy has been overlooked: the immune response. Normally, tumors grow faster than their blood supply, creating a hypoxic environment that stimulates cancer cells to produce a molecule called adenosine, which encourages antitumor T and NK cells to go into a dormant state.…”

“…HBO also promoted PD‐1 Ab delivery and T‐cell infiltration into the tumor parenchyma by depleting major components of the ECM, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia‐mediated immunosuppression and helps PD‐1 Ab trigger robust cytotoxic T lymphocyte responses and durable immune memory to suppress tumor recurrence 423,424 …”

The Normobaric Oxygen Paradox—Hyperoxic Hypoxic Paradox: A Novel Expedient Strategy in Hematopoiesis Clinical Issues

“…Genetical changes and uncontrolled cancer growth, which generate intra-tumor hypoxic areas (used by the innovative hypoxia-responsive drug delivery nanoplatforms [78]), cause HIF-1α overexpression enhancing neo-angiogenesis through VEGF synthesis and therefore favoring cancer progression and metastasis [79]. Only recently has the possible role of hyperoxia in tumor necrosis or development started to be investigated [80,81]. For example, leukemia cell lines exposed to a hyperoxic stimulus have been shown to increase the expression of caspase 3, and committing themselves to programmed death and apoptosis preceded morphological modifications of T and B cells [82].…”