This Research Topic focuses on the critical role of metabolic reprogramming in cancer cells and its influence on therapeutic responses, with particular emphasis on radiotherapy and chemo radiotherapy. Cancer metabolism, especially under hypoxic conditions, plays a pivotal role in modulating DNA repair, immune responses, and the tumor microenvironment, which can drive resistance to radiotherapy. Radiation-induced metabolic changes, including shifts in glycolysis, oxidative phosphorylation, and mitochondrial function, have profound effects on how cancer cells respond to the oxidative stress generated by radiotherapy, affecting their ability to repair DNA and survive.

Radiotherapy primarily induces DNA damage through reactive oxygen species (ROS), which cause double-strand breaks in cancer cell DNA. The success of radiotherapy often depends on the ability of cancer cells to repair this damage, a process that is strongly influenced by their metabolic state. Cells that undergo metabolic reprogramming - particularly in the context of hypoxia - typically exhibit altered DNA damage response (DDR) pathways, leading to treatment resistance. Beyond its direct impact on DNA repair, metabolic reprogramming also impacts the immune response to radiation therapy. Radiation has the potential to activate immune responses by promoting immunogenic cell death and enhancing antigen presentation, but cancer cells can adapt metabolically to evade this effect. For example, metabolic by-products such as lactate and adenosine that accumulate in the tumor microenvironment after radiotherapy can inhibit the function of immune cells such as cytotoxic T cells and macrophages, leading to immune suppression.

This article collection explores how targeting metabolic pathways involved in DDR can enhance radio sensitivity, rendering cancer cells more vulnerable to radiation-induced damage, while also examining how post-radiotherapy metabolic shifts in the tumor microenvironment contribute to immune evasion and resistance, with potential strategies to improve the efficacy of combined radiotherapy and immunotherapy.

In addition, dynamic metabolic changes induced by radiotherapy may create new, targetable bottlenecks in cancer cells. By understanding how radiotherapy alters metabolic pathways - such as the increased reliance on glycolysis under hypoxic conditions - researchers may be able to identify metabolic vulnerabilities that can be exploited for therapeutic gain. The issue will encourage research into how these treatment-induced metabolic changes can be used to design new therapeutic regimens that improve radio sensitivity or overcome resistance.

Submissions are encouraged on topics such as:

• The role of metabolic pathways in modulating DDR and cancer cell survival, specifically following radiotherapy.
• Dynamic metabolic changes induced by radiotherapy and how they create targetable vulnerabilities.
• Hypoxia-induced metabolic shifts that affect radiotherapy resistance.
• Metabolic control of immune responses in the tumor microenvironment post-radiation.
• Novel biomarkers of metabolic adaptation linked to radiotherapy outcomes.
• Therapeutic strategies targeting cancer metabolism to improve radiotherapy efficacy.

This Research Topic aims to integrate research from radiation biology, oncology, immunology and metabolism to explore how metabolic regulation influences radiotherapy outcomes. By examining both intrinsic and treatment-induced metabolic changes, the collection aims to identify strategies to improve radiotherapy efficacy and combat treatment resistance. We welcome original research, reviews, and clinical studies that focus on how targeting metabolism can improve patient outcomes after radiation-based therapies.

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Frontiers in Oncology

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