Depression-related chronic stress promotes ovarian cancer progression via metabolic dysfunction and IRF1-mediated immune suppression.

Abstract

Depression is highly prevalent among patients with ovarian cancer, but its impact on tumor progression and the underlying mechanisms remain unclear. This study aimed to investigate the relationship between depression and ovarian cancer progression, and evaluate the potential therapeutic value of antidepressant drugs. Clinical data analysis of patients with ovarian cancer revealed a significantly elevated risk of depression in this population. Animal experiments using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) models have confirmed that depression-related chronic stress induces depressive-like behaviors in mice and is associated with significant enhancement of ovarian cancer growth and metastasis. Mechanistically, single-cell RNA sequencing and metabolomics demonstrated that chronic stress downregulated interferon regulatory factor 1 (IRF1) expression in tumor cells. IRF1 suppression inhibited the immune effector cells infiltration, such as macrophages, while inducing abnormal lipid metabolism and glutathione pathway dysfunction. Notably, combining antidepressant drugs with platinum-based chemotherapy reversed these pathological changes. This combination therapy upregulated IRF1 expression, restored CCR2macrophage infiltration, and delayed ovarian cancer progression in mice. Clinical validation further confirmed that high IRF1 expression was correlated with prolonged overall survival (OS) in patients with ovarian cancer. These findings suggest that depression may be associated with ovarian cancer progression by remodeling the immune-metabolic microenvironment. This study highlights antidepressant therapy combined with anti-tumor treatment as a potential strategy for ovarian cancer patients with comorbid depression.