Psychological distress as a host-state factor in cancer immunotherapy: clinical associations, neuroendocrine mechanisms, and future trial design

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have transformed the treatment of multiple solid tumours, yet durable benefit remains confined to a subset of patients. Tumour-intrinsic biomarkers explain only part of this variability, highlighting the need to consider host-level determinants of antitumour immunity. Psychological distress, including depressive and anxiety symptoms, is common in patients with cancer and is potentially modifiable. In this review, we appraise clinical evidence linking pretreatment distress with ICI outcomes, with the principal clinical evidence coming from the prospective STRESS-LUNG cohort, the PRADO melanoma post-hoc analysis, and an individual patient-data meta-analysis of atezolizumab trials. Collectively, the available clinical evidence more strongly supports a general prognostic association, while an ICI-specific predictive effect has not been demonstrated. We then examine mechanistic evidence linking experimental chronic stress and stress-responsive signalling to sympathetic β-adrenergic and hypothalamic–pituitary–adrenal-axis pathways. These pathways can affect CD8 + T cells, dendritic cells, tumour cells, and the tumour microenvironment in preclinical and translational models. We also discuss psychosocial intervention, β-adrenergic blockade, and serotonergic modulation. For each approach, clinical evidence remains more limited than the mechanistic rationale. Existing evidence supports psychological distress as a clinically important and potentially modifiable host factor associated with inferior outcomes after checkpoint blockade, but does not establish that distress reduction improves ICI efficacy. Randomized, biomarker-informed studies are needed to determine whether modifying distress-related pathways can alter ICI outcomes, rather than simply identify patients with poorer prognosis.