The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT

Purpose: Hypoxia (low oxygen) is a common feature of solid tumours that has been intensely studied for more than six decades. Here we review the importance of hypoxia to radiotherapy with a particular focus on the contribution of hypoxia to immune responses, metastatic potential and FLASH radiotherapy, active areas of research by leading women in the field. Conclusion: Although hypoxia-driven metastasis and immunosuppression can negatively impact clinical outcome, understanding these processes can also provide tumour-specific vulnerabilities that may be therapeutically exploited. The different oxygen tensions present in tumours and normal tissues may underpin the beneficial FLASH sparing effect seen in normal tissue and represents a perfect example of advances in the field that can leverage tumour hypoxia to improve future radiotherapy treatments

Mutations in an innate immunity pathway are associated with poor overall survival outcomes and hypoxic signaling in cancer

Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators. We hypothesize that the same selective pressure could lead to complement alterations at the genetic level. We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types. Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer. The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55. The range of strategies employed by tumors to dysregulate the complement system testifies to the importance of this pathway in tumor progression