Little by little, we are seeing new studies call (timidly) for a “paradigm shift” (read: euphemism for massive failure) in medicine when it comes to cancer prevention and treatment. While the focus for the last 100+ years has been on genetics and (less so) to carcinogen exposure of carcinogenic infections (e.g. hepatitis), the fact that virtually no progress has been made in the cancer field over the last 50+ years calls for a dramatic shift in approach. Chronic stress is viewed by oncology as little more than nuisance, important only to the degree to which it can influence a cancer patient’s mental health, and even then psychiatry claims that a person’s vulnerability to stress is largely genetic. Medicine is still likely decades away from viewing stress as a true carcinogen, but the study below directly makes that claim. More specifically, it found that chronic stress (to which virtually all modern societies are exposed) directly drives HCC by shifting the metabolism of the amino acid L-tryptophan towards a pathway that produced immunosuppressive and inflammatory metabolites, which allows HCC to form, or to grow more aggressively if already present.
https://doi.org/10.1038/s42255-025-01446-z
Chronic Stress Drives Liver Cancer via Tryptophan Metabolism
“…The researchers employed a multidisciplinary approach combining metabolomics, transcriptomics, and in vivo liver cancer models to delineate this complex relationship. Their data demonstrated that chronic stress induces significant upregulation of hepatic enzymes responsible for tryptophan catabolism via the kynurenine pathway. Unlike the serotonin pathway, which modulates neural function, the kynurenine pathway’s metabolites are potent bioactive molecules that can influence immune responses, oxidative stress, and cellular proliferation within the liver microenvironment.”
“…Crucially, elevated kynurenine levels were found to suppress local immune surveillance mechanisms by activating aryl hydrocarbon receptors (AhR) in hepatic immune cells. This immunosuppressive milieu enables early neoplastic cells to evade destruction and promotes an environment conducive to malignant transformation. The study uncovered that this stress-induced metabolic switch does not occur in isolation but is tightly intertwined with systemic neuroendocrine signals, including corticosteroid release from the hypothalamic-pituitary-adrenal axis, further exacerbating hepatic tryptophan dysregulation. Furthermore, the authors provide compelling evidence showing that inhibition of key enzymes in the kynurenine pathway, such as indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2), significantly reduces tumor burden in murine models subjected to chronic stress. These findings not only confirm causality but also illuminate novel therapeutic targets that could disrupt the pathological sequence linking malaise and malignancy.”
“…The clinical implications of these findings are profound. Chronic stress, prevalent in modern society due to socioeconomic pressures, mental health disorders, and lifestyle factors, could be an underestimated driver of liver cancer incidence. Traditionally, liver cancer risk assessments have focused primarily on viral hepatitis, alcohol abuse, and metabolic syndromes. This study advocates for incorporating stress management and metabolic biomarkers into early diagnostic paradigms, potentially heralding an era where psychological health is considered integral to oncology prevention strategies.”
“…In concluding, Clarke, Keane, and Cryan’s work represents a paradigm shift that bridges psychiatry, metabolism, and oncology. It underscores the importance of viewing chronic stress as a multifaceted biological stressor with tangible consequences beyond the nervous system, extending deep into hepatic cellular metabolism and cancer biology. This integrative perspective paves the way for holistic strategies that encompass psychological health, metabolic regulation, and targeted cancer therapies.”
