Depression and shortened survival in patients with cancer: a neuroimmune framework for bidirectional pathogenesis and...

Although depression is highly prevalent among patients with cancer and is consistently linked to shortened survival, its underlying biological mechanisms remain incompletely understood. While emerging evidence suggests that depression reshapes both systemic and tumor-localized immunity via β-adrenergic and glucocorticoid signaling, the broader integrative pathways remain to be fully defined. To address this gap, this review synthesizes evidence from clinical, epidemiological, and translational studies to present a unifying systems-level framework: depression influences cancer outcomes through the coordinated dysregulation of the autonomic nervous system (ANS), hypothalamic-pituitary-adrenal (HPA) axis, and neuroimmune network. Collectively, this triad fosters a pro-tumorigenic microenvironment. Unlike simpler linear models, this framework emphasizes the coupled, self-reinforcing interactions among these three systems. Specifically, sympathetic overdrive combined with vagal withdrawal amplifies the HPA output, peripheral inflammation sustains central dysregulation, and brain-derived neurotrophic factor (BDNF) dysfunction impairs neuroendocrine feedback. Herein, we critically evaluate the evidence supporting each node of this triad and highlight persistent controversies and evidence gaps, particularly regarding causal directionality and the translational divide between preclinical and human studies. Furthermore, we propose a targeted research agenda introducing three testable endophenotypes (HPA-dominant, inflammation-dominant, and cytotoxicity-dominant) designed to guide future biomarker-stratified immuno-oncology trials. We argue that while restoring autonomic-neuroendocrine-immune homeostasis represents a promising, testable strategy to improve survival, any related therapeutic recommendations remain strictly investigational until validated in large-scale randomized controlled trials with survival endpoints.