Hypoxia is a state of low oxygen concentration within tissues and it is a common phenomenon among solid tumors, as the vasculature cannot supply sufficient oxygen to the increased proliferation rate of cancer cells.

Intratumoral hypoxia is a dynamic status that differs in a spatio-temporal manner and is usually classified into two categories: chronic and acute hypoxia. Chronic hypoxia refers to a low oxygen tension that lasts more than 24h, mainly due to cell over-proliferation and consequently increased distance between some tumor cells and the blood vessels. Tumor mass increase could also obstruct small blood vessels, causing a lack of oxygenation. This phenomenon is defined as acute hypoxia and usually is resolved within a few hours by regaining the blood flow.

While normal cells cannot survive prolonged hypoxic conditions, in cancer cells the low-oxygen state triggers pro-survival genes expression resulting in enhanced angiogenesis, cellular proliferation, and invasion. Furthermore, hypoxia has been found associated with cancer-treatment resistance and poor prognosis. The main drivers of the hypoxia-induced cellular response are the hypoxia-inducible factors (HIFs). HIFs are a family of heterodimeric transcription factors composed of an oxygen-dependent regulatory alpha subunit and a constitutively expressed nuclear beta subunit.

Given its major role in several pro-tumorigenic processes, therapeutic strategies to selectively target tumor hypoxia have attracted considerable attention. HIF subunits seem the most tantalizing targets for anti-cancer drugs, and while direct pharmacological targeting remains elusive, several drugs have shown anti-tumoral effects by modulating the activity and/or the level of HIFs.

Other promising therapeutic options are hypoxia-activated prodrugs (HAPSs), bioactive compounds which can be reduced under hypoxic conditions to generate cytotoxic compounds. HAPs are designed to specifically target the hypoxic cells within the tumor and could play a major role in overcoming resistance to traditional cancer therapies.

To date, despite encouraging preclinical and early clinical phase results, the implementation of hypoxia-targeting drugs in the clinic has not been very successful. This lack of impact could be explained considering the redundancy and heterogeneity of hypoxia-response pathways and the complex interplay between the tumor and its microenvironment.

This Research Topic aims to provide new insights into the therapeutic strategies to target the cancer cell response to hypoxia. We welcome submissions that focus on, but not limited to, the following themes:

- Molecular mechanisms underlying hypoxia-induced therapy resistance
- Strategies to improve radiotherapy response in hypoxic tumors
- Hypoxia targeting gene expression for cancer gene therapy
- Novel hypoxia-related therapeutic targets, such as HIF-mediated cellular survival targets
- The impact of hypoxia on the anti-tumor immune response
- Pre-clinical and clinical trials

Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.

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Frontiers in Oncology

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