Stress and cancer immunotherapy: distress linked to poorer checkpoint inhibitor outcomes

Patients with cancer who carry a heavy burden of psychological distress may fare worse on immune checkpoint inhibitors, the drugs that have transformed the treatment of melanoma, lung cancer and many other solid tumours. That is the central conclusion of a review published in Frontiers in Oncology, which pulls together the clinical cohorts, animal experiments and intervention studies that have accumulated over the past few years around one deceptively simple question: does the mind of the patient shape the immune response that these drugs are designed to unleash? The authors, Guanwen Lin and Zhilin Luo, conclude that the answer is a cautious and qualified yes for association, but a firm no for causation.

Immune checkpoint inhibitors block inhibitory molecules such as PD-1, PD-L1 and CTLA-4, releasing the brakes on exhausted T cells. In a subset of patients with non-small-cell lung cancer, melanoma, renal cell carcinoma and other malignancies, this produces durable disease control that cytotoxic chemotherapy rarely achieved. Yet durable benefit remains the exception rather than the rule, and the biomarkers in routine clinical use, including PD-L1 immunohistochemistry, tumour mutational burden and microsatellite instability, explain only a fraction of the variation in response. The resistance mechanisms mapped so far are overwhelmingly tumour-intrinsic: impaired antigen presentation, altered interferon signalling, T-cell exclusion and the accumulation of regulatory T cells and suppressive myeloid cells. The review argues that host-level factors, extrinsic to the tumour, deserve equal attention as potential upstream modifiers of these established resistance states.

Psychological distress is common in oncology. A meta-analysis of interview-based studies placed the prevalence of major depression at around one in six patients, with some form of mood disorder affecting 30 to 40 percent of patients in hospital settings, and prevalence varying by tumour type, sex and age. Depression has been associated with increased cancer mortality across tumour types in successive meta-analyses, through biological routes such as persistent systemic inflammation, hypothalamic-pituitary-adrenal axis dysregulation and impaired cellular immunity, and through behavioural routes such as delayed presentation, reduced adherence and adverse health behaviours. What remained largely untested until recently was whether these same processes are associated with the efficacy of immunotherapy specifically, a treatment whose success depends on systemic and intratumoural host immune activity rather than on tumour-intrinsic features alone.

The strongest clinical evidence comes from the prospective STRESS-LUNG cohort, which enrolled 227 patients with advanced non-small-cell lung cancer starting first-line checkpoint inhibitor-based therapy. Emotional distress, defined before treatment as a PHQ-9 score of 5 or higher and/or a GAD-7 score of 5 or higher, was present in 111 patients, nearly 49 percent. On the primary endpoint, patients with distress had a median progression-free survival of 7.9 months compared with 15.5 months in those without, a hazard ratio of 1.73. Secondary endpoints were concordant: an objective response rate of 46.8 percent versus 62.1 percent, and a two-year overall survival of 46.5 percent versus 64.9 percent, with poorer quality-of-life scores throughout. Because the study was observational, these findings establish association rather than causation.

The same cohort offered a biological clue. In an exploratory analysis of 210 patients, blood drawn at 8 a.m. before treatment showed that baseline cortisol was higher in distressed patients, 443.4 versus 386.0 nanomoles per litre, while ACTH did not differ significantly. Using the cohort median cortisol level as the cut-off, median progression-free survival was 7.8 months in the high-cortisol group versus 12.6 months in the low-cortisol group, and higher cortisol was also associated with a greater risk of overall survival events. The authors of the review stress that these findings remain observational and do not establish cortisol as a mediator between distress and immunotherapy outcome.

Convergent signals have emerged from other designs. A post-hoc analysis of the phase 2 PRADO trial of neoadjuvant ipilimumab plus nivolumab in stage III melanoma found that baseline distress, identified with the EORTC emotional-functioning scale, was associated with a lower major pathological response rate, 46 percent versus 65 percent, and lower two-year relapse-free and distant-metastasis-free survival, after adjustment for the interferon-gamma signature and tumour mutational burden. An individual patient-data meta-analysis of 4,632 patients across seven atezolizumab trials in lung cancer found that emotional distress was associated with worse overall survival, with a hazard ratio of 1.18, and progression-free survival, with a hazard ratio of 1.15, and the point estimate was identical in the immunotherapy and chemotherapy cohorts. The authors of that analysis concluded that distress is a prognostic biomarker rather than an ICI-specific predictive one, although a formal treatment-by-distress interaction test was not reported. A separate aggregate meta-analysis of eight studies and 911 patients pooled an overall survival hazard ratio of 1.85, but only two of the included studies were ICI-based and certainty was rated low to very low.

On the mechanistic side, the review distinguishes carefully between clinical distress measured in patients and experimental chronic stress induced in animals. In murine models, chronic stress activates the sympathetic nervous system and the HPA axis, and both pathways can reshape antitumour immunity. Exhausted CD8+ T cells upregulate the beta-1 adrenergic receptor, and catecholamine exposure suppresses cytokine production and proliferation in these cells; ablation of beta-1 signalling, genetically or with the beta-1-selective blocker atenolol, limited T-cell progression towards exhaustion and improved effector function when combined with checkpoint blockade in melanoma and colon-cancer models. Other work implicates the beta-2 adrenergic receptor in metabolic dysfunction of CD8+ T cells, and housing-temperature stress has been shown to undermine checkpoint inhibitor efficacy through beta-2-adrenergic activation. The relative contribution of the two receptor subtypes in human tumour-infiltrating T cells remains uncertain, which complicates the interpretation of clinical beta-blocker data.

Glucocorticoid signalling acts on both sides of the immune synapse. The glucocorticoid receptor is highly expressed by dysfunctional tumour-infiltrating CD8+ T cells, where it transactivates the inhibitory receptors PD-1, TIM-3, LAG-3 and TIGIT along with the immunosuppressive cytokine interleukin-10, and active glucocorticoid signalling marks failure to respond to checkpoint blockade in both murine models and melanoma patients. Stress-induced glucocorticoids also induce the gene TSC22D3 in dendritic cells, blocking type I interferon responses and compromising therapy-induced antitumour immunity, while in pancreatic cancer models glucocorticoid-receptor signalling in tumour cells upregulates PD-L1 and represses MHC class I, with receptor inhibition reversing both effects and overcoming resistance to checkpoint blockade.

Translating these mechanisms into treatment has so far disappointed. A phase 1 study of propranolol with pembrolizumab in nine patients with metastatic melanoma established safety and a recommended phase 2 dose but could not assess efficacy, and retrospective analyses of patients already taking beta-blockers alongside immunotherapy have yielded mixed results vulnerable to confounding. Pooled analyses, including a systematic review of 12 studies and 4,293 patients, found no significant survival benefit from adding beta-blockers to checkpoint inhibitors. Psychosocial interventions reliably reduce anxiety and depression and improve quality of life, and a meta-analysis in breast cancer reported reductions in cortisol after such intervention, but no adequately powered randomized trial has tested whether they improve immunotherapy efficacy as measured by survival. Serotonergic approaches are even earlier in translation: in preclinical models, inhibition of the serotonin transporter on tumour-infiltrating T cells synergized with PD-1 blockade, but whether antidepressant use modifies immunotherapy outcomes in patients remains unresolved and confounded by the depression for which these drugs are prescribed.

The review’s bottom line is deliberately restrained. Pretreatment psychological distress is associated with poorer outcomes in most, though not all, cohorts, and the evidence more strongly supports a general prognostic association than an ICI-specific predictive effect. Reverse causation remains possible, since more advanced disease can both generate distress and worsen survival, and residual confounding by performance status, comorbidity, inflammation and treatment adherence is difficult to exclude observationally. The authors argue that distress screening and psychosocial care should be part of supportive cancer care on their own merits, because distress is common, clinically important and affects patient well-being, but that such care should not currently be presented as a strategy to improve immunotherapy response. What is needed, they conclude, are randomized, biomarker-informed trials with prespecified treatment-by-distress interaction analyses, longitudinal distress measurement and neuroendocrine biomarker stratification, designed to determine whether modifying distress-related pathways can genuinely alter immunotherapy outcomes rather than simply identify patients with a poorer prognosis.

Subject of Research: The association between psychological distress and outcomes of immune checkpoint inhibitor therapy in cancer, and the neuroendocrine mechanisms that may underlie it.

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

Article References: Lin, G., & Luo, Z. (2026). Psychological distress as a host-state factor in cancer immunotherapy: clinical associations, neuroendocrine mechanisms, and future trial design. Frontiers in Oncology, 16, Article 1899935. https://doi.org/10.3389/fonc.2026.1899935

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1899935

Keywords: immune checkpoint inhibitors, psychological distress, PD-1, cancer immunotherapy, HPA axis, cortisol, beta-adrenergic signalling, CD8 T cells, tumour microenvironment, prognostic biomarker, psycho-oncology, NSCLC