The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence

Key Points Radiotherapy is a common treatment option for cancer patients. However, many aspects of the tumour microenvironment (TME) can render a tumour resistant to radiotherapy de novo or can lead it to recur with a worse prognosis following therapy. Normal tissue toxicity limits the dose of radiotherapy that can be safely delivered. Combination strategies are required in order to achieve better tumour control. Radiotherapy-mediated immunogenic cell death (ICD) can elicit an immune response, but antitumour immunity may be limited owing to the presence of radioresistant suppressor cell types in the TME. Combining radiotherapy and immunomodulatory treatments may overcome adaptive immune suppression and holds great promise both locally in the primary tumour and abscopally. Hypoxia has a crucial role in radioresistance owing to reduced oxygen-mediated fixation of DNA damage and hypoxia induced factor 1α (HIF1α)-mediated cell survival. Attempts to increase oxygen delivery, normalize tumour vessels, inhibit HIF1α and prevent the recruitment of bone marrow-derived cells (BMDCs) required for vasculogenesis are all being tested to reduce tumour hypoxia, improve radiotherapy responses and prevent tumour recurrence after therapy. Tumour irradiation induces a wound healing response that is characterized by inflammation, cancer-associated fibroblast (CAF) modulation and extracellular matrix (ECM) remodelling, which may facilitate tumour recurrence. Targeting the initial inflammatory response may counteract attempts to boost the immune-mediated antitumour response following radiotherapy. Therefore, reducing ECM remodelling by inhibiting growth factors, receptor kinases or matrix enzymes may be more effective in preventing the post-irradiation stiffening of the TME that could facilitate tumour spread. Careful scheduling of tumour reoxygenation strategies with radiotherapy will be required to maximize tumour control. Subsequent inclusion of immunomodulatory and anti-fibrotic treatments should be considered to maximize therapeutic benefits and to prevent post-irradiation tumour recurrence and metastasis. In this Review, Barker and colleagues describe the mechanisms of radioresistance that are mediated by the tumour stroma and explore how these mechanisms can be targeted to improve radiotherapy responses. Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological eff