Impact of Baseline Nutritional Status, Psychological Health, Fatigue, and Insomnia on Outcomes of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Retrospective Cohort Study.

1
Introduction
Lung cancer remains the leading cause of cancer‐related mortality worldwide, accounting for 11.6% of all cancer cases, with non‐small cell lung cancer (NSCLC) representing approximately 85%–87% of all lung cancer diagnoses [1, 2]. Until recently, treatment options for advanced‐stage NSCLC primarily involved combination chemotherapy, providing a progression‐free survival (PFS) of 4–6 months and an overall survival (OS) of around 12–18 months [3]. The emergence of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape, significantly improving outcomes for select patients [3, 4]. ICIs, such as pembrolizumab, tislelizumab, and atezolizumab, target the PD‐1/PD‐L1 pathway to enhance immune surveillance and anti‐tumor responses [5]. Treatment regimens are often guided by PD‐L1 expression levels, with patients exhibiting high tumor proportion scores (TPS ≥ 50%) receiving monotherapy and others requiring chemoimmunotherapy or dual ICI combinations [6]. Despite these advancements, clinical outcomes remain highly variable. While tumor PD‐L1 expression serves as a key biomarker, it is insufficient to fully predict responses. Emerging evidence suggests that patient‐specific factors, such as nutritional status and systemic inflammation, can significantly affect ICI efficacy, as shown by associations between low BMI or high PLR and poorer survival outcomes [7, 8]. Nutritional status, psychological health, and specific physical symptoms have gained attention for their potential roles in modulating immunotherapy outcomes. However, the mechanisms underlying these associations remain unclear, and their implications for clinical practice are underexplored.
Nutritional status, often assessed using the Controlling Nutritional Status (CONUT) score, is a critical determinant of immune competence [9]. Poor nutritional status has been associated with systemic inflammation, reduced lymphocyte activity, and impaired anti‐tumor immunity, all of which can compromise treatment efficacy. Poor nutritional status, for instance, has been linked to systemic inflammation, immune suppression, and adverse oncologic outcomes [10]. For example, high CONUT scores have been linked to shorter survival times in NSCLC patients undergoing surgical or medical treatment, suggesting its prognostic value extends to immunotherapy [11].
Psychological health, including anxiety, depression, and hope, has also emerged as a key modulator of immune function and cancer outcomes. Chronic psychological distress may dysregulate the hypothalamic–pituitary–adrenal axis, leading to elevated cortisol levels, increased systemic inflammation, and suppressed anti‐tumor immunity [12, 13]. Hope, on the other hand, is associated with better psychological resilience and may indirectly enhance immune responses and treatment adherence [14]. Understanding the interplay between these psychological factors and immunotherapy efficacy could provide valuable insights for developing holistic care strategies.
Additionally, specific symptoms such as cancer‐related fatigue and insomnia are highly prevalent in NSCLC patients and have been shown to negatively affect quality of life and functional status. Fatigue, driven by systemic inflammation and metabolic disruptions, may impair physical activity and immune recovery, while insomnia can disrupt circadian rhythms and immune homeostasis [15, 16]. These symptoms, though often overlooked, may serve as modifiable predictors of treatment outcomes.
While these factors have been investigated individually in various cancer settings, their combined impact on immunotherapy outcomes in advanced NSCLC remains underexplored. A comprehensive understanding of how baseline nutritional, psychological, and symptomatic factors influence PFS and OS could guide the development of targeted interventions, including nutritional optimization, psychosocial support, and symptom management, to improve patient outcomes.
This retrospective study aims to evaluate the relationships between baseline nutritional status, psychological health, fatigue, and insomnia with treatment response, PFS, and OS in advanced NSCLC patients treated with ICIs monotherapy. By leveraging validated assessment tools, this study seeks to identify actionable prognostic factors and inform a more personalized and holistic approach to NSCLC management. The findings may provide a basis for integrating supportive care interventions alongside immunotherapy to enhance both survival and quality of life for these patients.

2
Methods and Materials
2.1
Ethics Statement
This retrospective study was approved by the Ethics Committee of the hospital. Informed consent was waived due to the retrospective nature of the research and the use of de‐identified patient data. The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.

2.2
Enrolled Patients
To reduce selection bias inherent to retrospective studies, all eligible patients who received ICI monotherapy between June 2020 and June 2024 were consecutively included based on predefined clinical and laboratory criteria. All treatments were administered following national guidelines and standard clinical practice, enhancing the generalizability and real‐world applicability of the findings. First‐line monotherapy options included pembrolizumab, atezolizumab, or tislelizumab for tumors with PD‐L1 expression ≥ 50%, following standard dosing schedules: pembrolizumab 200 mg every 3 weeks, atezolizumab 1200 mg every 3 weeks, or tislelizumab 200 mg every 3 weeks. Second‐line monotherapy was offered following failure of first‐line chemoimmunotherapy, including pembrolizumab for tumors with PD‐L1 > 1% (200 mg every 3 weeks), or atezolizumab and tislelizumab regardless of PD‐L1 status, administered at their respective standard doses.

2.3
Inclusion and Exclusion Criteria
Eligible patients were aged ≥ 18 years with measurable disease per RECIST v1.1, assessed by CT within 1 month before starting immunotherapy, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2, and adequate liver and renal function (bilirubin, alkaline phosphatase, and transaminase < 1.5× upper normal limits; sodium > 125 mmol/L; normal calcium; creatinine clearance > 40 mL/min). Patients were enrolled irrespective of the completeness of baseline assessment data (e.g., questionnaires/scores) or subsequent treatment outcomes. Patients were excluded if they had active malignancies other than NSCLC, EGFR/ALK/ROS1 mutation‐positive NSCLC, active autoimmune diseases, thyroiditis, hypophysitis, acute cardiac failure, unstable angina, symptomatic brain metastases requiring high‐dose steroids, or seropositivity for hepatitis B, hepatitis C, or HIV. Pregnancy, lactation, cognitive impairment (Mini‐Mental State Exam ≤ 23) [17], and substance abuse disorders were also exclusion criteria.

2.4
Collection of Patient‐Reported Baseline Data Prior to ICIs Monotherapy
The data on nutritional status, psychological health, fatigue, and insomnia were originally documented in the medical records as part of routine clinical assessment prior to the initiation of ICI therapy. These data, recorded by trained clinical staff during initial consultations, were retrospectively extracted and analyzed for the purpose of this study. The Controlling Nutritional Status (CONUT) score assessed nutritional risk based on serum albumin, total cholesterol, and lymphocyte count, reflecting protein reserves, energy stores, and immune function. Scores range from 0 (no risk) to 12 (severe risk), with < 2 indicating low risk and ≥ 2 signifying higher nutritional risk or potential malnutrition [18]. Hope was measured using the 12‐item Herth Hope Index (HHI), which evaluates interconnectedness, positive readiness and expectation, and awareness of temporality and the future. Participants rated items on a 4‐point Likert scale (1 = “strongly disagree” to 4 = “strongly agree”), with total scores ranging from 12 to 48; higher scores reflect greater hope [14]. As no established cut‐off exists, the study used the median score of the enrolled patients for group stratification. Psychological distress, encompassing anxiety and depression, was assessed with the Hospital Anxiety and Depression Scale (HADS), a validated tool commonly used in cancer populations [19]. Each subscale includes seven items rated on a 4‐point scale, with scores > 7 indicating clinically significant anxiety or depression [20]. Fatigue was evaluated using the Brief Fatigue Inventory (BFI), a widely used measure for cancer‐related fatigue. The BFI comprises nine items: three on fatigue severity (0 = “no fatigue” to 10 = “worst imaginable fatigue”) and six on the impact of fatigue on daily activities (0 = “does not interfere” to 10 = “completely interferes”) [21]. Patients were categorized based on a global fatigue score cut‐off of ≥ 4 [22]. The Athens Insomnia Scale (AIS), an 8‐item self‐report questionnaire based on ICD‐10 criteria, assessed nocturnal sleep and daytime dysfunction. Scores range from 0 to 24, with higher scores indicating more severe insomnia; a cut‐off score of 6 was applied [16, 23].

2.5
Clinical Outcomes
The study evaluated treatment response, progression‐free survival (PFS), and overall survival (OS) in all patients starting from the initiation of ICI therapy. Tumor response was assessed according to RECIST 1.1 [24], with the first evaluation performed at week eight. Response categories included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). PFS was defined as the time from the start of ICI therapy to either the first documented disease progression or death from any cause, whichever occurred first. OS was defined as the time from treatment initiation to death from any cause. Patients without progression or death at the time of analysis were censored at their last follow‐up. All patients were followed until death or the end of the follow‐up period (October 30, 2024).

2.6
Statistical Analysis
Statistical analyses were performed using SPSS version 21.0 (IBM Corp., Armonk, NY) and GraphPad Prism version 8.0 (GraphPad Software, San Diego, CA). Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR), depending on their distribution. Categorical variables were presented as counts and percentages. To evaluate the relationship between baseline characteristics (e.g., nutritional status, psychological health, fatigue, and insomnia) and immunotherapy response, Kruskal‐Wallis tests were applied for continuous variables, and post hoc comparisons were conducted using the Dunn‐Bonferroni correction. For survival analysis, Kaplan–Meier curves were generated to estimate OS and PFS, and differences between groups were assessed using the Log‐rank test. Prior to Cox regression modeling, multicollinearity among covariates was assessed using the variance inflation factor (VIF), with a VIF < 10 considered acceptable. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Statistical significance was set at p < 0.05 for all tests.

3
Results
3.1
Baseline Characteristics
The study enrolled 80 stage IV NSCLC patients (Table 1), predominantly male (66.3%); mean age 66.8 ± 9.0 years, BMI 20.1 ± 1.2 kg/m2, with adenocarcinoma as the major subtype (82.5%) and 43.8% having PD‐L1 ≥ 50%. ECOG scores were 0 (13.8%), 1 (52.5%), and 2 (33.8%). Among the 80 patients, 35 (43.8%) received ICI monotherapy as first‐line treatment, and 45 (56.3%) received ICI monotherapy in the second‐line setting. The median PFS was 10.5 months (mean 12.83 months; range 2–44 months), and the median OS was 20 months (mean 22.98 months; range 5–45 months). Baseline patient‐reported scores were as follows: CONUT (2.28 ± 1.89), HHI (39.68 ± 4.05), HADS‐Anxiety (4.06 ± 3.32), HADS‐Depression (5.71 ± 4.21), BFI (4.34 ± 1.53), and AIS (6.13 ± 3.38).

3.2
Pretreatment Nutritional Status, Psychological Health, Fatigue, and Insomnia Predict Response to ICIs in Advanced NSCLC
Of 80 patients, 28 showed partial response (PR), 29 had stable disease (SD), and 30 experienced progressive disease (PD). Compared to PR patients (Figure 1), PD patients had significantly worse nutritional status (CONUT median 3 vs. 1; p < 0.05), lower hope (HHI median 38 vs. 42; p < 0.05), higher anxiety (HADS‐A median 5 vs. 2; p < 0.05), depression (HADS‐D median 7 vs. 3; p < 0.05), fatigue (BFI median 6 vs. 3; p < 0.05), and insomnia (AIS median 8 vs. 3.5; p < 0.05). SD patients showed intermediate scores, with significant differences in CONUT, depression, and fatigue compared to PR (all p < 0.05). These findings highlight the importance of pretreatment nutritional and psychosocial factors in predicting response to immunotherapy in advanced NSCLC.

3.3
Pretreatment Nutritional Status, Psychological Health, Fatigue, and Insomnia Predict Prognosis in Advanced NSCLC Treated With ICIs
Low nutritional risk, higher hope, lower anxiety, lower depression, less fatigue, and milder insomnia significantly predicted improved survival in advanced NSCLC patients receiving ICIs. Patients with low nutritional risk showed longer median OS (36 vs. 19 months, p < 0.001) and PFS (18 vs. 6 months, p = 0.002) (Figure 2). Higher hope scores (HHI >40) were associated with prolonged OS (35 vs. 19 months, p = 0.001) and PFS (18 vs. 7 months, p = 0.002) (Figure 3A,B). Anxiety (HADS‐A > 7, Figure 3C,D) and depression (HADS‐D > 7, Figure 3E,F) significantly shortened OS (14 vs. 30 months and 17 vs. 35 months; both p < 0.001) and PFS (both 2 vs. 14 or 15 months; p < 0.001 and p = 0.007). Similarly, higher fatigue (BFI ≥ 4, Figure 4A,B) and severe insomnia (AIS ≥ 6, Figure 4C,D) significantly predicted worse OS (20 vs. 43 months and 19 vs. 36 months; both p < 0.001) and shorter PFS (8 vs. 28 months and 6 vs. 19 months; both p < 0.001).

3.4
Stratified Analysis of Pretreatment Nutritional Status, Psychological Health, Fatigue, and Insomnia Predicting Prognosis in Advanced NSCLC Patients Receiving ICIs According to Sex and Histology
As shown in Table S1, baseline factors significantly influenced survival with notable sex differences. In females, high CONUT scores (OS, p = 0.016; PFS, p = 0.008), low hope (OS, p = 0.006; PFS, p = 0.020), depression (OS, p < 0.001; PFS, p = 0.006), fatigue (OS, p = 0.008; PFS, p = 0.007), and insomnia (OS, p = 0.040; PFS, p = 0.012) predicted worse outcomes. In males, these factors had stronger associations, especially anxiety (OS, p < 0.001; PFS, p = 0.0002), depression (OS, p < 0.001; PFS, p = 0.029), fatigue (OS and PFS, p = 0.002), and insomnia (OS and PFS, p = 0.002). Moreover, these adverse effects were predominantly observed in adenocarcinoma patients (all p < 0.01), while in squamous cell carcinoma only anxiety (p < 0.001), depression (p = 0.005), and fatigue (PFS, p = 0.050) showed prognostic significance. This suggests greater sensitivity of adenocarcinoma patients to psychosocial and nutritional risks, emphasizing the need for targeted supportive care.

3.5
Cox Regression Analysis for PFS and OS in Advanced NSCLC Patients Receiving ICIs
Prior to conducting Cox regression analyses, multicollinearity among covariates was assessed using the VIF (data not shown). All variables exhibited acceptable VIF values below the commonly used threshold of 10, with most values under 3, indicating low to moderate collinearity. Although Treatment and TPS expression demonstrated slightly elevated VIFs (> 5), they remained within acceptable limits and were therefore retained for further analysis. Additionally, while some variables—such as CONUT, HHI, HADS‐A, HADS‐D, BFI, and AIS—may be conceptually interrelated due to their shared relevance to nutritional or psychosocial status, statistical assessment revealed no evidence of problematic collinearity. Thus, all candidate variables were included in the multivariate Cox models. As demonstrated in Tables 2 and 3, univariate Cox regression analysis identified several baseline factors significantly associated with both PFS and OS in advanced NSCLC patients receiving ICIs. Poor nutritional status, represented by higher CONUT scores (PFS: HR = 1.22, p = 0.002; OS: HR = 1.37, p < 0.001), and lower hope levels (HHI scores; PFS: HR = 0.91, p = 0.002; OS: HR = 0.87, p < 0.001) were significantly associated with worse outcomes. Psychological distress, including anxiety (HADS‐A; PFS: HR = 1.20, p < 0.001) and depression (HADS‐D; PFS: HR = 1.09, p = 0.002; OS: HR = 1.18, p < 0.001), as well as greater fatigue (BFI; PFS: HR = 1.45, p < 0.001; OS: HR = 1.62, p < 0.001) and insomnia severity (AIS; PFS: HR = 1.16, p < 0.001; OS: HR = 1.28, p < 0.001), were also significant predictors of reduced survival. Additionally, disease progression significantly correlated with poorer OS (HR = 4.55, p = 0.036). Significant factors from univariate analyses (p < 0.05) were included in multivariate Cox regression models. Multivariate analysis identified anxiety (HADS‐A; HR = 1.12, p = 0.015) as an independent predictor of shorter PFS, while depression (HADS‐D; HR = 1.09, p = 0.019) and fatigue (BFI; HR = 1.32, p = 0.033) remained independent predictors of reduced OS. These findings emphasize the clinical importance of pretreatment nutritional and psychosocial assessments to better predict prognosis in advanced NSCLC patients treated with ICIs.

4
Discussion
This study emphasizes the critical influence of baseline nutritional status, psychological health, fatigue, and insomnia on clinical outcomes in advanced NSCLC patients undergoing ICIs monotherapy. Key findings revealed that higher nutritional risk (elevated CONUT scores), greater psychological distress (higher HADS‐A and HADS‐D scores), fatigue, and insomnia were associated with significantly worse PFS and OS. Notably, anxiety was an independent predictor of PFS, while depression and fatigue independently predicted OS. Conversely, higher levels of hope were strongly associated with improved survival outcomes, underscoring the prognostic value of both physiological and psychosocial factors.
Pretreatment nutritional status emerged as a pivotal determinant of survival. Patients with high nutritional risk had poorer PFS and OS, likely due to the interplay between malnutrition, systemic inflammation, and immune dysfunction. Prior studies corroborate the prognostic significance of the CONUT score in lung cancer. For instance, Onodera et al. linked high preoperative CONUT scores in resectable NSCLC to worse OS and recurrence‐free survival, mediated by adverse pathological features like pleural invasion and lung metastasis [11]. Similarly, Yilmaz et al. identified CONUT as an independent predictor of OS and PFS in small cell lung cancer [25]. Gul et al. found that poor nutritional status, as assessed by the CONUT and PNI scores, is a prevalent factor associated with significantly reduced overall survival in both NSCLC and SCLC patients with locally advanced and advanced‐stage lung cancer [26]. These findings suggest that early nutritional optimization, through dietary counseling or supplementation, may enhance the immune response and improve immunotherapy outcomes.
Advance NSCLC patients receiving immunotherapy or chemoimmunotherapy in clinical practice reported higher symptom prevalence [27]. Psychological health, particularly anxiety and depression, also played a significant role in survival outcomes. Elevated HADS‐A and HADS‐D scores were associated with poorer PFS and OS, respectively. Chronic psychological distress is known to dysregulate the hypothalamic–pituitary–adrenal axis and sympathetic nervous system, leading to elevated cortisol levels and pro‐inflammatory cytokines, which impair immune surveillance and tumor suppression [12, 28]. The findings of Gui et al. further highlight how psychological distress adversely impacts the tumor microenvironment and immune system, suggesting potential therapeutic targets [29]. Interventions such as cognitive‐behavioral therapy and pharmacological treatments could address psychological distress, positively influencing immunotherapy efficacy and survival outcomes.
Fatigue and insomnia were another significant predictor of worse survival outcomes. Hopkins et al. demonstrated that patient‐reported fatigue and global health outperform ECOG‐PS and LIPI in predicting OS, emphasizing the importance of incorporating symptom assessments into clinical care [30]. Addressing these symptoms through evidence‐based strategies, such as energy conservation techniques, physical therapy, or sleep hygiene education, could optimize treatment responses and improve quality of life. Lastly, hope emerged as a protective factor in this study. Patients with higher HHI scores exhibited significantly better PFS and OS, consistent with findings from Hsu et al., who identified hope as a modifiable factor influenced by fatigue and insomnia and treatment cycles [14]. Mechanistically, hope and psychological resilience may enhance immune competence, further improving survival. These insights support the integration of psychosocial interventions to bolster hope, alleviate distress, and optimize outcomes in NSCLC patients undergoing ICIs monotherapy.
This retrospective study has several limitations. First, the potential for selection bias and the relatively small sample size may restrict the generalizability of the findings. Second, the observational, single‐arm design precludes causal inference and limits the ability to definitively determine whether the identified prognostic factors, such as nutritional status, psychological health, fatigue, and insomnia, directly influence the efficacy of ICIs or represent general prognostic markers for advanced NSCLC. Thus, our results should be interpreted as hypothesis‐generating, highlighting potential prognostic associations rather than definitive predictive relationships. Third, detailed genetic profiling data (e.g., EGFR, KRAS, STK11, or KEAP1 mutations), which are known to influence ICI outcomes, were not available for all patients due to the retrospective nature of the study. As such, we were unable to explore potential interactions between genetic alterations and clinical or psychosocial variables. Fourth, although we adjusted for key clinical characteristics, unmeasured confounders, such as comorbidities, socioeconomic status, prior therapies, and concurrent medications, could have influenced immune function and treatment outcomes. Fifth, although several psychosocial and nutritional variables—such as CONUT, HHI, HADS‐A, HADS‐D, BFI, and AIS—may be conceptually interrelated, formal multicollinearity analysis using the VIF revealed no significant statistical collinearity. Nonetheless, the possibility of underlying conceptual overlap should be considered when interpreting the results. Future research should employ prospective designs, include comparator arms (e.g., chemotherapy‐treated patients), and account for a wider range of clinical, molecular, and psychosocial covariates to minimize residual confounding. Tailored interventions targeting these modifiable baseline factors may ultimately enhance survival and therapeutic benefit in patients with advanced NSCLC.

5
Conclusion
Baseline nutritional status, psychological health, fatigue, and insomnia were significantly associated with survival outcomes in advanced NSCLC patients receiving ICI monotherapy. Although our observational findings do not establish a causal relationship or confirm treatment‐specific predictive value, addressing these modifiable factors through targeted interventions could pave the way for more comprehensive and effective cancer care, improving both survival outcomes and quality of life.

Conflicts of Interest
The authors declare no conflicts of interest.

Supporting information

Table S1: Stratified analysis of baseline factors predicting prognosis in advanced NSCLC patients receiving ICIs according to sex and histology.