Emotional distress: the hidden barrier to immunotherapy success in advanced non-small cell lung cancer
Shannon Zhang1, Shiyao Wang2, Zhaohui Liao Arter1
Keywords: Non-small cell lung cancer (NSCLC); emotional distress (ED); immunotherapy
Submitted Jan 09, 2025. Accepted for publication Apr 02, 2025. Published online May 14, 2025.
doi: 10.21037/tlcr-2025-31
The intersection of emotional distress (ED) and cancer treatment efficacy represents a compelling frontier in oncological research. The recent study published in Nature Medicine explores the significant association between pretreatment ED and the clinical efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC) (1). These findings not only reveal a potential psycho-biomarker for treatment stratification but also a call for an integrative approach to cancer care.
Receiving a cancer diagnosis leads to ED, which can negatively impact a patient’s quality of life (QoL). Approximately half of all cancer patients experience fatigue (55.7%) and ED (47.7%) per the NEOETIC_SEOM study (2). Fatigue and ED explained 61% of the variance in QoL (3). These symptoms may continue to last beyond treatment and into survivorship (4). Cancer patients also have a higher prevalence (×2 higher) of suicide compared to patients without cancer, especially within the first six months of diagnosis (5). ED and cancer have also been shown to possess a mutually reinforcing relationship, making it a difficult cycle to break (6).
Chronic stress has been linked to dysregulation of the immune system by lowering the antibody and cell mediated immune response (7). This is in part due to consistent activation of the hypothalamic-pituitary-adrenal (HPA) axis, which ultimately leads to T lymphocyte and neutrophil apoptosis, and reduced function of CD8 T cells and natural killer (NK) cells (7). ICIs have improved outcomes across many cancer subtypes, including advanced NSCLC. Recent studies have shown that the psychological condition of a patient may influence responses to immunotherapy (8,9).
The STRESS-LUNG-1 study, a prospective observational study of 227 patients, provides compelling evidence of this link (1). ED was identified using the patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder 7-item (GAD-7) scale. In the cohort, 48.9% of patients met the diagnosis for ED. Results showed patients with ED had a significantly shorter progression-free survival (PFS) (7.9 months) compared to patients without ED [15.5 months, hazard ratio (HR) 1.73; 95% confidence interval (CI): 1.23–2.43, P=0.002], consistent across all subgroups. The objective response rate (ORR) was also lower in patients with ED (46.8%) compared to those without (64.9%, HR 1.82; 95% CI: 1.12–2.97, P=0.016). These findings suggest that ED in advanced-stage NSCLC patients is associated with poorer outcomes when treated with ICIs. As this was consistent across all subgroups, it suggests that the ED itself impacts the response to immunotherapy. We hypothesize that impaired immune response due to stress may explain this phenomenon. While it is assumed that cancer patients may have worse outcomes with ED, there is limited data specifically evaluating cancer response to immunotherapy in ED.
This study is the first to evaluate the relationship between ED and ICIs response in advanced cancer patients, paving the way for future research. Despite the pivotal findings of this study, several limitations have been identified.
First, the study is a single-center observational study, which may limit its generalizability to other geographical locations. All patients were Chinese, with the majority (92.5%) being male and having a current or former smoking history (87.2%). To account for differences inherent to race and cultural backgrounds, additional data from diverse ethnic groups are necessary. It is possible that a second confounding factor exists in the group with a higher level of ED (i.e., lower socioeconomic class, poor nutritional intake, poor adherence), which may lead to poorer outcomes. Thus, it would be interesting to see if a similar study with a non-immunotherapy class of drug (i.e., chemotherapy or targeted therapy) would lead to similar results. More data are also needed to evaluate outcomes in females and non-smokers.
Second, the study utilized various ICIs, including pembrolizumab, atezolizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, and sugemalimab. This heterogeneity in therapeutic agents may have introduced variability in patient responses and influenced the overall outcomes.
Third, the study did not account for certain patient comorbidities, such as chronic pain syndrome, which could influence stress levels and serve as confounding factors.
Fourth, the GAD-7 and PHQ-9 forms are self-reported assessment tools and several of the questions focus on somatic symptoms that are common in cancer patient population, such as fatigue, sleep difficulties, reduced concentration, and poor appetite. Therefore, a more specific evaluation system for depression or anxiety in the medically ill population may be needed.
Lastly, comorbid substance use disorder is commonly seen alongside mental illness and should be assessed and treated in conjunction with mental health diagnoses.
Another study evaluated the association between ED and neoadjuvant ICIs response in stage IIIB–D melanoma (10). This study used a different method, the European Organization for Research and Treatment of Cancer scale, for identifying ED. This scale particularly evaluates ED in cancer patients, unlike in the STRESS-LUNG-1 study, where more generic scales for anxiety and depression are utilized. This study found that pretreatment ED led to a significantly reduced pathologic response (46% versus 65%) and reduced 2-year distant metastasis-free survival (78% versus 91%) compared to patients without pretreatment ED after adjusting for interferon-gamma (IFNγ) and tumor mutation burden (TMB). This study had a smaller sample size of 85. Both studies utilized cortisol levels and found that elevated cortisol levels were associated with adverse outcomes, raising the question of whether there is any utility in trending cortisol levels as a secondary method to measure ED, given the subjective nature of self-guided questionnaires. A prior review also noted that increased cortisol may increase or exacerbate other comorbid conditions including diabetes and hypertension, which may also be another confounding factor in decreasing prognosis in cancer patients (6). Some suggest looking into the gut microbiome or utilizing beta blockers to improve outcome in cancer patients who are treated with ICIs (11). Specifically, gut Bacteroides stercoris and TME macrophages may be related to the relationship between ED and ICIs efficacy, although further research is needed (12).
Additional prospective observational cohort studies will also explore the relationship between psychologic stress and efficacy of therapy. Specifically, STRESS-LUNG-2 will study the relationship between psychological stress and efficacy of first-line treatment of limited-stage and extensive-stage small cell lung cancer (SCLC). Patients will be eligible if they have stage III–IV SCLC and are systematic treatment naïve, receiving programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors monotherapy with combination chemotherapy. Primary outcome is the time from first-line immunotherapy to first progression as with the STRESS-LUNG-1 cohort. The STRESS-LUNG-3 cohort explores the relationship between psychological stress and efficacy of neoadjuvant ICIs in resectable NSCLC. Primary outcome is pathologic complete response rate. STRESS-LUNG-4 studies the relationship between psychologic stress with cancer progression and prognosis of NSCLC receiving radical surgery with primary outcome being duration between date after surgery to date of recurrence or death, firstly. Follow-up period for all cohorts will be 5-year with estimated 750 patients enrolled (Table 1). All cohorts will evaluate psychologic stress based on PHQ-9 and GAD-7 questionnaires. We eagerly anticipate results of these studies to see if psychological distress decreases efficacy of ICIs in other settings.
Table 1
| Trial | Primary/secondary endpoints | Other outcome measures | Patients for accrual | Eligibility criteria† | Follow-up period | NCT registration |
|---|---|---|---|---|---|---|
| STRESS-Lung 1 | Primary: time from 1st line immunotherapy to 1st PD | Correlation between gut microbiota, tumor microenvironment, peripheral stress biomarker and chronic stress, efficacy of ICIs | 750 | Unresectable locally advanced, metastatic, recurrent stage IIIB–IV NSCLC, ECOG 0–1, systematic treatment naïve, at least 1 measurable lesion, receiving PD-1/PD-L1 inhibitors monotherapy or combination with chemotherapy | 5 years | NCT05477979 |
| Secondary: OS, QoL, ORR | ||||||
| STRESS-Lung 2 | Primary: time from 1st line immunotherapy to 1st PD | Correlation between gut microbiota, tumor microenvironment, peripheral stress biomarker and chronic stress, efficacy of ICIs | 750 | Unresectable locally advanced, metastatic, recurrent stage III–IV SCLC, ECOG 0–1, at least 1 measurable lesion, receiving PD-1/PD-L1 inhibitors monotherapy or combination with chemotherapy | 5 years | NCT05477979 |
| Secondary: OS, QoL, ORR | ||||||
| STRESS-Lung 3 | Primary: pCR rate | Correlation between gut microbiota, tumor microenvironment, peripheral stress biomarker and chronic stress, efficacy of ICIs | 750 | Resectable clinical stage IB–IIIB NSCLC, at least 1 measurable lesion, systematic treatment naïve, receiving PD-1/PD-L1 inhibitors combined with chemotherapy as neoadjuvant | 5 years | NCT05477979 |
| Secondary: OS, QoL, ORR | ||||||
| STRESS-Lung 4 | Primary: duration between surgery to date of recurrence/death | Correlation between gut microbiota, tumor microenvironment, peripheral stress biomarker and chronic stress, efficacy of ICIs | 750 | Early stage IA–IIIA NSCLC, available for tumor tissue samples, systematic treatment naïve, receiving radical surgery | 5 years | NCT05477979 |
| Secondary: OS, QoL, ORR |
†, eligibility criteria for all: age ≥18 years; measurable lesion per RECIST v1.1; staging per AJCC TNM staging 8th edition. AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; ICIs, immune checkpoint inhibitors; NCT, national clinical trial; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; pCR, pathologic complete response; PD, progression of disease; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; QoL, quality of life; RECIST, Response Evaluation Criteria in Advanced Solid Tumors; SCLC, small cell lung cancer; TNM, tumor-node-metastasis.
As all patients in STRESS-LUNG-1 were Chinese, it will be pivotal to conduct similar studies across different patient populations. Given the diverse patient population in the United States, performing trials across cancer centers within the region could enhance the generalizability of these findings. As similar outcomes have been reported in melanoma patients as previously described, there remains a significant knowledge gap in the evaluation of this hypothesis in other solid cancer types that are often treated with immunotherapy, such as but not limited to colorectal, head and neck, bladder, renal, and hepatobiliary. In one study, patients who had psychological distress were found to have increased cervical cancer specific mortality than those who did not (13). Another review article discusses the findings that increased levels of stress were associated with an increase in breast and ovarian cancer progression (14). Beyond immunotherapy, future studies could explore how ED affects susceptibility to other treatment modalities such as chemotherapy or targeted therapies, especially as an increasing number of targeted therapies are being utilized in modern day oncology.
In conclusion, STRESS-LUNG-1 highlights the crucial role of addressing ED and optimizing mental health in cancer patients. This study introduces the first “psycho-biomarker” to predict the efficacy of ICIs in NSCLC. Moving forward, multi-center and global studies involving diverse populations are essential. We urge oncologists to assess mental health from the initial evaluation and throughout treatment. Early involvement of multidisciplinary support teams, including palliative care, psychologists, psychiatrists, and social workers, is vital for improving outcomes. Further research is needed to determine if treating ED can significantly enhance overall outcomes, given the potential for prolonged resolution times. Wu and her team are conducting the BRIO study (ClinicalTrials.gov; identifier: NCT05979818) to evaluate the efficacy and safety of combining β-blockers with ICIs and chemotherapy in first-line therapy for advanced-stage NSCLC, with results eagerly awaited.
Acknowledgments
We extend our sincere gratitude to Dr. Sai-Hong Ignatius Ou for his invaluable guidance and support.
Footnote
Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-31/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-31/coif). Z.L.A. reports serving on the advisory board for Catalyst. The other authors have no conflicts of interest to declare.
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References
- Zeng Y, Hu CH, Li YZ, et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med 2024;30:1680-8. [Crossref] [PubMed]
- Rodriguez-Gonzalez A, Velasco-Durantez V, Martin-Abreu C, et al. Fatigue, Emotional Distress, and Illness Uncertainty in Patients with Metastatic Cancer: Results from the Prospective NEOETIC_SEOM Study. Curr Oncol 2022;29:9722-32. [Crossref] [PubMed]
- Abdelhadi O. The impact of psychological distress on quality of care and access to mental health services in cancer survivors. Front Health Serv 2023;3:1111677. [Crossref] [PubMed]
- Fernando A, Tokell M, Ishak Y, et al. Mental health needs in cancer - a call for change. Future Healthc J 2023;10:112-6. [Crossref] [PubMed]
- Morey JN, Boggero IA, Scott AB, et al. Current Directions in Stress and Human Immune Function. Curr Opin Psychol 2015;5:13-7. [Crossref] [PubMed]
- Pecci F, Tarantino P. Patient-focused insights: how emotional distress shapes immunotherapy response in non-small cell lung cancer. Transl Lung Cancer Res 2024;13:3819-23. [Crossref] [PubMed]
- Aguilar EJ, Ricciuti B, Gainor JF, et al. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann Oncol 2019;30:1653-9. [Crossref] [PubMed]
- Tian W, Liu Y, Cao C, et al. Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments. Front Cell Dev Biol 2021;9:777018. [Crossref] [PubMed]
- Bi Z, Li W, Zhao J, et al. Negative correlations of psychological distress with quality of life and immunotherapy efficacy in patients with advanced NSCLC. Am J Cancer Res 2022;12:805-15. [PubMed]
- Fraterman I, Reijers ILM, Dimitriadis P, et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nat Med 2023;29:3090-9. [Crossref] [PubMed]
- Schor J. Stress May Weaken Immunotherapy Action. Natural Medicine Journal. 2024. Available online: https://www.naturalmedicinejournal.com/journal/stress-may-weaken-immunotherapy-action
- Wu F, Zeng Y, Zhou J. P4.15D.04 Association Between Emotional Distress and Immunotherapy Response in Advanced NSCLC (STRESS-LUNG-1): Biomarkers Exploratory Analyses. J Thorac Oncol 2024;19:S417. [Crossref]
- Lu D, Andrae B, Valdimarsdóttir U, et al. Psychologic Distress Is Associated with Cancer-Specific Mortality among Patients with Cervical Cancer. Cancer Res 2019;79:3965-72. [Crossref] [PubMed]
- Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Future Oncol 2010;6:1863-81. [Crossref] [PubMed]
