Chronic stress: a fourth etiology in tumorigenesis?

Chronic stress, driven by persistent psychological, environmental, or physiological factors, is a prolonged heightened state of stress response that disrupts homeostasis. When unmanaged, it will lead to sustained negative emotions such as depression, loneliness, anxiety, and emotional adversity. This persistent emotional distress not only exacerbates mental health disorders but also poses significant risks to physical health. Increasing evidence suggests a strong link between chronic stress, stress-related hormones, and the rising incidence of malignancies. As a result, chronic stress might be recognized as a potential “fourth etiology” of cancer, alongside physical, chemical, and biological carcinogens. As a potential etiological driver of tumorigenesis, chronic stress-related hormones such as glucocorticoids and catecholamines or neurotransmitters have been implicated in various aspects of tumor initiation, promotion, and progression. Additionally, chronic stress influences tumorigenesis through multiple mechanisms, including tumor microenvironment remodeling, microbial dysbiosis, drug resistance promotion, as well as the regulation of oncogenic signaling pathways. Hence, mitigating the impact of chronic stress could be an effective method of cancer prevention and therapy. However, it remains a significant challenge in the assessment of chronic stress as a cancer etiology. Moreover, the link between stress-associated obesity and cancer offers novel insights into underlying mechanistic pathways in cancer research. Repurposing preventive and therapeutic approaches targeting stress-related tumorigenesis may provide deeper insights into the interplay between chronic stress and cancer, ultimately improving patient outcomes and quality of life.