Using a convenience sampling method, the study involved lung cancer patients receiving immune checkpoint inhibitor treatment, both inpatients and outpatients, from a tertiary cancer specialist hospital in Guangzhou from October 2020 to January 2021. Inclusion criteria: 1) Pathologically confirmed diagnosis of lung cancer; 2) Stages II, III, or IV lung cancer according to the 8th edition of the TNM staging criteria issued by the Union for International Cancer Control in 2017; 3) Aged 18 years or older; 4) Currently receiving monotherapy or combination therapy with immune checkpoint inhibitors; 5) Able to understand, read, or write in Chinese; 6) Gave informed consent to participate in this study. Exclusion criteria: 1) Patients with a past or current diagnosis of mental illness or cognitive impairment; 2) Undisclosed condition: Patients unaware of their condition; 3) Patients currently participating in clinical trials; 4) Patients with coexisting other tumors. A total of 191 patients were effectively surveyed, and their general information is shown in Table 1 .

This questionnaire was designed by the researchers based on a literature review and includes sociodemographic information and disease-related data. The sociodemographic information is filled out by the patients and verified by the investigator through medical records. The disease and treatment-related data are completed by the investigator by reviewing the medical records.

The questionnaire consists of two parts. The first part includes 16 core symptom items related to cancer treatment, selected from the Chinese version of the Treatment-Related Symptoms Checklist developed and localized by the Williams team [6] . The second part is an immune module, which initially added 30 possible symptoms related to immune checkpoint inhibitor (ICI) treatment based on a literature review and clinical consultations. An expert consultation method was used to evaluate and filter these symptom items. Incorporating the experts’ suggestions and preliminary survey results from patients, 18 symptoms highly related to ICI treatment were selected to form the immune module for measuring symptoms and severity in lung cancer patients undergoing ICI treatment.

The content validity of the initial questionnaire was reviewed by medical and nursing experts in immunology and lung cancer treatment, and its Content Validity Index (CVI) was obtained, including the item-level CVI (I-CVI) and the scale-level CVI (S-CVI). The final questionnaire consists of 34 items in total. Scoring follows the TRSC scoring rules, using a Likert 5-point scale, where symptoms are rated from 0 (no symptoms) to 4 (very severe), and the sum of the item scores is the total score; a higher score indicates more severe symptoms. Expert evaluation showed that the I-CVI for each item of the questionnaire ranged from 0.67 to 1.00, and the S-CVI ranged from 0.83 to 1.00. In this study, the reliability coefficient (Cronbach’s α) for the questionnaire was 0.80, and the I-CVI ranged from 0.67 to 1.00.

The MCMQ, developed by Feifel H [7] , is a tool suitable for measuring coping styles in patients with various diseases. It includes three dimensions: confrontation, avoidance, and acceptance-resignation, with a total of 19 items. It was translated and revised by Shen Xiaohong [8] in 2000 into 20 items, divided into three coping strategies and dimensions: confrontation, avoidance, and resignation. It uses a Likert 4-point scale, scored from 1 to 4, with higher scores indicating a greater tendency for individuals to adopt that coping style. The Cronbach’s α coefficients for the dimensions are 0.69, 0.60, and 0.76, respectively. This questionnaire has been widely used in cancer patient research [8] [9] . In this study, the overall internal consistency of Cronbach’s α is 0.80, with consistency for the dimensions being 0.75, 0.60, and 0.85.

The GAD-7, developed by Spitzer et al. [10] in 2006, is a 7-item scale for screening generalized anxiety and assessing symptom severity. It uses a Likert 4-point scale, where 0 represents “not at all,” and 3 represents “nearly every day,” with scores ranging from 0 to 21. Scores of 0 - 4 indicate no anxiety, 5 - 9 mild anxiety, 10 - 14 moderate anxiety, and 15 or above severe anxiety, with higher scores indicating more severe anxiety symptoms [11] . Domestic studies show that the GAD-7’s Cronbach’s α coefficient is 0.90, and the retest reliability coefficient is 0.76, indicating good reliability and validity [12] . In this study, Cronbach’s α coefficient is 0.89.

The PHQ-9 is a 9-item self-report scale revised based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) for depression screening. It uses a Likert 4-point scale, where 0 represents “not at all,” and 3 represents “nearly every day,” with scores ranging from 0 to 27. Higher scores indicate more severe depression symptoms: 0 - 4 for no depression, 5 - 9 for the presence of depressive symptoms, 10 - 14 for significant depressive symptoms, and 15 or above for severe depression [13] . Studies show that the PHQ-9’s Cronbach’s α coefficient is 0.839 [14] . In this study, the Cronbach’s α coefficient is 0.79.

The study design is cross-sectional. The objective is to investigate symptoms and their influencing factors in lung cancer patients receiving immune checkpoint inhibitor therapy. Based on prior experience and relevant literature review, the estimated standard deviation is 29.72. A two-tailed test is required with α = 0.05 and a permissible error of 5. The sample size is calculated using the following formula: n = (Zα² * σ²)/δ². The calculated sample size N = 136. Considering a 10% non-response rate, this study requires a minimum of 150 participants. After obtaining informed consent, questionnaires were completed and collected on-site. A total of 193 surveys were completed for this study, with 191 valid questionnaires collected, resulting in an effective recovery rate of 99.0%.

SPSS 25.0 was used for statistical description of the data. 1) Descriptive statistics were conducted on patients’ physiological, psychological, and environmental data using frequency, composition ratio, mean ± standard deviation; symptom scores were described using frequency, composition ratio, median, and interquartile range. 2) Univariate analysis: Since all data were non-normally distributed, the rank-sum test was used for metric data, and the chi-square test was used for categorical data to make statistical inferences. 3) Correlation analysis: Coping styles, anxiety, and depression were normally distributed after testing, so Pearson correlation analysis was used to explore the relationship between patients’ symptoms and coping styles, anxiety, and depression. 4) Multiple linear regression analysis was employed to explore the influencing factors of patient symptoms, with the total symptom score as the dependent variable. The significance level was set at α = 0.05, and a two-tailed test with P < 0.05 was considered statistically significant.

The symptom score for lung cancer patients treated with immune checkpoint inhibitors was (24.35 ± 10.32), with the incidence of different symptoms ranging from 12.0% to 93.2%. For patients receiving a combination of ICIs and other treatment plans, the symptom score was (26.01 ± 9.93), with the incidence of different symptoms ranging from 11.3% to 92.5%. For patients receiving ICI monotherapy, the symptom score was (16.09 ± 8.15), with the incidence of different symptoms ranging from 0% to 96.9%. A total of 70 (36.6%) patients in this study reported experiencing 16 other symptoms independently, as detailed in Table 1 and Table 2 .

Note: The scores for all 34 symptoms surveyed do not conform to a normal distribution.

According to the normality test, all the physiological factors and social environment factors in this study did not conform to the normal distribution. Therefore, the rank sum test was used to analyze the data of different physiological factors, including gender, body mass index BMI and receiving treatment. The difference in treatment was statistically significant. The Kruskal-Wallis method was used for pairwise comparison between groups. Among the variables with statistically significant differences in Table 3 , it was found that the symptom scores for females were significantly higher than for males (P < 0.01); patients with a BMI < 18.4 had higher symptom scores than those with a BMI ≥ 18.5 (P < 0.05); patients receiving ICIs combined with chemotherapy had significantly higher symptom scores than those receiving ICIs alone (P < 0.01); and patients with a monthly household income per capita < 2000 yuan had higher symptom scores than those with a per capita monthly income > 2000 yuan (P < 0.01).

Note: *: P < 0.05, **: r < 0.01.

Patient symptom scores were positively correlated with the “acceptance-resignation” dimension of medical coping styles, anxiety, and depression, as detailed in Table 4 and Table 5 .

Note: *: P < 0.01.

Note: *: P < 0.01.

Using the total symptom score of lung cancer patients treated with immune checkpoint inhibitors as the dependent variable, variables with significant results in the univariate analysis and Pearson correlation analysis were used as independent variables. Dummy variables were assigned to multicategory variables and entered using the enter method, while other binary and quantitative variables were handled using the stepwise method to construct a multiple linear regression analysis model. The assignments of independent variables in the multiple linear regression model are shown in Table 6 . The results of the regression analysis are shown in Table 7 .

Note: The Durbin-Watson statistic is 1.804, F = 12.422, P < 0.001**; P < 0.05*; P < 0.01, Adjusted R² = 0.375.

Patients with lung cancer treated with immune checkpoint inhibitors bear a significant symptom burden. The most common symptoms include fatigue, decreased mental state, poor sleep quality, urinary abnormalities, loss of appetite, taste changes, dry mouth, cough, hair loss, itching, depression, skin changes, a feeling of fullness, decreased interest in sex, and pain. For patients receiving ICI monotherapy, the top five symptoms were fatigue, decreased mental state, dry mouth, poor sleep quality, and urinary abnormalities; for those receiving ICIs combined with other treatments, the top five symptoms were fatigue, poor sleep quality, decreased mental state, loss of appetite, and urinary abnormalities.

In this study, the incidence of skin changes was 53.9%, and the incidence of skin itching was 57.1%. Skin changes mainly included itching, rash, pigmentation, dryness (peeling, flaking), and capillary hyperplasia. Previous researchers have considered skin changes to be mainly due to the skin toxicity of antitumor drugs [5] [15] . The incidence of symptoms in lung cancer patients treated with ICIs monotherapy and ICIs combined with other treatments is not entirely the same. Compared with combined treatment plans, patients receiving ICI monotherapy reported a lower incidence and severity of gastrointestinal symptoms such as nausea and vomiting, but more often reported skin symptoms such as rash and itching. Currently, for mild to moderate (grade 1 - 2) skin-related symptoms, clinical approaches typically involve the topical use of emollients, oral antihistamines, and/or topical medium-potency corticosteroids for symptomatic treatment [5] [16] [17] . More severe (grade 3 - 4) skin symptoms are rare and generally require the suspension of ICI treatment and active treatment with high-potency corticosteroids topically, or consultation with dermatology experts and systemic corticosteroid therapy [5] [16] [17] .

In this study, among the symptoms reported by patients, the presence of Reactive Cutaneous-Capillary Endothelial Proliferation (RCCEP) showed a statistically significant difference with the use of the immune checkpoint inhibitor drug Camrelizumab (χ² = 144.258, P < 0.01). Patients treated with Camrelizumab exhibited scattered “red mole” type spots or “tumor-like” growths on the facial area, head and neck, and trunk. Patients commonly self-assessed the severity as grade 1 - 2, and these spots were prone to rupture with difficult bleeding control after rupture. Therefore, patients using Camrelizumab should be informed in advance that RCCEP might appear on the skin surface during the first cycle after the initial drug administration (2 - 4 weeks). RCCEP is rarely observed on oral and nasal mucosa and generally will self-resolve or persist until 1 - 2 months after drug cessation. This information can prevent patients from experiencing undue anxiety [17] - [19] . For patients with RCCEP, careful observation and patient education are essential. Patients should be informed that RCCEP is prone to rupture and uncontrollable bleeding, so they should wear soft clothing and avoid scratching or rubbing the affected area. In cases of bleeding, applying pressure or using Yunnan Baiyao powder can help stop it. For “tumor-like” RCCEP lesions that affect daily life, laser treatment or surgical removal may be performed [18] [19] .

In the multiple linear regression analysis of this study, the physiological factors influencing patient symptoms with statistical significance were BMI and the current treatment method. Psychological factors included depression and the “acceptance-resignation” dimension of medical coping styles.

1) Body Mass Index (BMI)

BMI directly reflects the nutritional status of patients. In this study, there were statistically significant differences in symptoms among patients with different BMI levels. Patients with a BMI of 17.4 - 18.5 kg/m² were included in the multiple linear regression equation, indicating that underweight patients had a higher incidence or more severe symptoms, consistent with previous studies [20] [21] . Research on lung cancer patients shows that underweight and obese patients have higher postoperative complications compared to those with normal BMI, and the functional and nutritional status of patients influences the prognosis and quality of life [20] - [24] . The better the basic physiological and nutritional condition of patients, the higher their tolerance to tumors and antitumor treatments [22] [25] . Therefore, in clinical practice, patients with a BMI outside the normal range, especially those below the normal level, should receive nutritional interventions, such as guidance on a high-protein, easily digestible diet, and, if necessary, oral nutritional supplements like protein powder. This helps maintain a normal BMI, enhancing tolerance to antitumor treatments and reducing symptom occurrence and progression [26] [27] .

2) Current Treatment Method

The results of this study indicate that the treatment plan is an important predictor of total symptom score. Compared to ICIs monotherapy and ICIs combined with targeted therapy, patients receiving ICIs combined with chemotherapy and ICIs combined with chemotherapy and targeted therapy had higher total symptom scores. This is because chemotherapy for lung cancer patients is highly toxic, the chemotherapy cycles are generally long, and most undergo long-term maintenance chemotherapy, which has been associated with more severe symptoms as the duration increases [6] [28] [29] . In the univariate analysis, the current treatment method had a statistically significant difference with total symptom scores (P < 0.01). Inter-group comparisons showed statistical significance in total symptom scores between ICIs combined with chemotherapy and ICIs monotherapy and between ICIs combined with targeted therapy (P < 0.05), suggesting that the overall symptoms of ICIs combined with chemotherapy patients are more severe than those treated with ICIs monotherapy or ICIs combined with targeted therapy, consistent with current research findings [29] . Therefore, there should be an emphasis on the prevention and management of symptoms in patients receiving ICIs combined with chemotherapy.

1) Coping Styles

Coping styles are a cognitive appraisal between stressors and behavioral interventions, affecting people’s response types and intensity to stressful events, and regulating their adaptation processes and outcomes. Positive adaptive coping styles have a beneficial impact on health outcomes, whereas maladaptive negative coping styles negatively affect individuals’ health outcomes. It has been reported that postoperative lung cancer patients adopting negative coping styles are more prone to depressive symptoms [30] ; lung cancer patients using positive coping styles have higher quality of life levels and perceive less pain, with acceptance-resignation coping styles having the greatest impact on comfort levels during chemotherapy [31] . An optimistic coping style is significantly negatively correlated with cancer-related fatigue in breast cancer patients, while emotional and fatalistic negative coping styles are significantly positively correlated with fatigue in cognitive dimensions [32] .

The results of this study found that acceptance-resignation is a predictor of total symptom scores (P < 0.05), with more severe treatment-related symptoms found in those using acceptance-resignation coping styles. Acceptance-resignation is a common negative emotional coping style among cancer patients, characterized by a pessimistic and hopeless attitude towards the disease, believing they cannot control its progression, avoiding communication with medical staff, and eventually abandoning treatment compliance (e.g., not taking medication on time, refusing rehabilitation activities), even falling into self-blame and self-pity. This coping style is not merely a “negative emotion” but adversely affects symptom management by reducing treatment adherence, increasing psychological burden, lowering quality of life, and diminishing psychological resilience, thus seriously impacting patients’ health outcomes [33] - [36] . In clinical practice, psychological interventions (such as cognitive behavioral therapy, relaxation training, group psychotherapy) are needed to help patients change their coping styles and develop positive coping strategies (e.g., confronting, seeking support) to improve their health outcomes [37] [38] .

2) Depression

This study found that depression is a risk factor for the severity of symptoms in lung cancer patients. The higher the depression score, the higher the total symptom score, which is consistent with previous research [39] - [41] . As one of the common negative emotions in cancer patients, depression, as a psychological factor, affects patients’ perception and experience of the disease and symptoms. Patients with higher levels of depression are more sensitive to symptom perception and experience, often manifesting through somatization [42] [43] . Depression exacerbates the symptom burden in lung cancer patients through multiple mechanisms. On one hand, depression can lead to immune function suppression (such as inducing apoptosis of immune cells and inhibiting antigen presentation), worsening the body’s inflammatory response to tumors, thereby exacerbating physical symptoms like pain and dyspnea [39] [40] [44] . On the other hand, the negative emotions of depressed patients (such as anxiety and hopelessness) create a vicious cycle of “low mood → less willingness to cooperate with treatment → symptom deterioration.” Depressed patients may abandon regular treatment (e.g., missing medication, refusing rehabilitation training), leading to tumor progression or unmanaged treatment side effects (e.g., nausea, hair loss from chemotherapy), thereby increasing the symptom burden [44] [45] . Additionally, depression can lower the pain threshold, making patients more sensitive to physical symptoms like pain, further amplifying symptom perception. In clinical practice, it is important to emphasize depression screening and intervention for lung cancer patients [46] . Early identification of depressive symptoms and timely psychological (such as cognitive-behavioral therapy or supportive psychotherapy) or pharmacological interventions (such as antidepressants) can improve patients’ emotional states and alleviate their symptom burdens (such as somatic symptoms and lung cancer-specific symptoms), enhancing quality of life [39] .