Highlighting the Potential for Chronic Stress to Minimize Therapeutic Responses to Radiotherapy through Increased Immunosuppression and Radiation Resistance

Simple Summary Stress is an integral part of life and is necessary for proper development and function of every organ. However, there is growing evidence that prolonged activation of the sympathetic stress response stress negatively affects the outcome of many diseases including cancer and impairs the efficacy of widely used therapies. In this review, we specifically focus on the potential mechanisms by which chronic stress could inhibit the efficacy of radiation therapy. We conclude that there is significant evidence for increased suppression of anti-tumor immune responses along with induction of tumor cell survival pathways. Because cancer patients are susceptible to many sources of stress, including stress associated with anxiety and depression, this survey provides a strong rationale for implementing stress-reduction strategies in patients who will be receiving radiation therapy. Ionizing radiation has been used in the treatment of cancer for more than 100 years. While often very effective, there is still a great effort in place to improve the efficacy of radiation therapy for controlling the progression and recurrence of tumors. Recent research has revealed the close interaction between nerves and tumor progression, especially nerves of the autonomic nervous system that are activated by a variety of stressful stimuli including anxiety, pain, sleep loss or depression, each of which is likely to be increased in cancer patients. A growing literature now points to a negative effect of chronic stressful stimuli in tumor progression. In this review article, we present data on the potential for adrenergic stress to influence the efficacy of radiation and in particular, its potential to influence the anti-tumor immune response, and the frequency of an "abscopal effect" or the shrinkage of tumors which are outside an irradiated field. We conclude that chronic stress can be a major impediment to more effective radiation therapy through mechanisms involving immunosuppression and increased resistance to radiation-induced tumor cell death. Overall, these data highlight the potential value of stress reduction strategies to improve the outcome of radiation therapy. At the same time, objective biomarkers that can accurately and objectively reflect the degree of stress in patients over prolonged periods of time, and whether it is influencing immunosuppression and radiation resistance, are also critically needed.