The incidence of head and neck cancer (HNC) has risen to sixth place among all tumors worldwide (1, 2). Radiotherapy (RT), which is a traditional antitumor method, plays an irreplaceable role in HNC treatment. The role of immune checkpoint blockade (ICB) in the treatment of HNC is increasing. The combination of RT and ICB has been hailed as a new dawn for antitumor treatment (3). The long-term effects of treatment are of concern in survivors. Most studies have shown that HNC survivors struggle with distress and depression in addition to a large variety of persistent cancer-related symptoms (4, 5). Higher rates of anxiety and depression symptoms are found in patients with HNC because of their unique tumor location (6). Integrated supportive care, especially cognitive-behavioral therapy (CBT) and mindfulness-based interventions, could help patients identify and modify negative thought patterns and behaviors and thus alleviating psychological distress (7, 8). Notably, anxiety and depression in these patients not only diminish quality of life but also might affect antitumor therapeutic efficacy. For example, Zeng et al. and Fraterman et al. reported an association between emotional distress and worse clinical outcomes in advanced non-small cell lung cancer and melanoma patients receiving ICB treatment (9, 10). This finding indicated an intrinsic link between emotional distress and ICB treatment. On the one hand, the undifferentiated attack of ICB often induces immune-related adverse events. On the other hand, immune checkpoint blockade might activate common immune-dependent repair mechanisms. However, to our knowledge, no studies have investigated the associations of the combination of RT and ICB with depression and anxiety in HNC patients.

Between October 9, 2020, and December 6, 2023, stage III-IV HNC patients undergoing intensity-modulated radiotherapy (IMRT) were recruited from Shandong Cancer Hospital and Institute. All male and female participants provided informed consent. The inclusion criteria were as follows: (1) new diagnosis of stage III-IV stage head and neck cancer (nasopharynx, larynx, oropharynx, or hypopharynx) according to the eighth AJCC and pathological staging; and (2) concurrent chemotherapy and radiotherapy treatment. (3) Combined ICB patients must receive ICB therapy (PD-1 and PD-L1 inhibitors) during or before RT. (4) Control patients must never receive ICB therapy before or after RT. The exclusion criteria were as follows: (1) had multiple primary cancers, (2) had prior irradiation, and (3) could not cooperate with the relevant evaluation and follow-up of the study.

All patients received daily IMRT treatment using 2.0 Gy fractions. The total dose range was 48–76 Gy. Patients were divided into 3 groups: RT + chemotherapy ± targeted drug group (control group), ICB + sequential RT + chemotherapy ± targeted drug group (ICB + sRT group) and RT + chemotherapy ± targeted drug + concurrent ICB group (ICB + cRT group). ICB drugs include PD-1 inhibitors (camrelizumab, pembrolizumab, toripalimab, sintilimab, tislelizumab) and a PD-L1 inhibitor (adebrelimab). The main outcomes considered were anxiety and depression scores on the Hospital Anxiety and Depression Scale (HADS) (11). Originally designed as a self-assessment tool for detecting depression and anxiety, the HADS is now extensively utilized in both nonhospital settings and research studies. The assessment includes 14 questions, with seven evaluating anxiety and seven evaluating depression, resulting in two subscale scores. Each question is rated on a scale from 0 to 3, where a higher score signifies a greater severity of mood disorder. No missing data were present for HADS scores or covariates, and a complete-case approach was naturally applied. Patients completed questionnaires by email, postal mail or phone on Feb. 01, 2024. We adopted 1:1 propensity score matching (PSM) via the nearest-neighbor matching method to minimize between-group heterogeneity and selection bias for the control group vs. the ICB + sRT group, the control group vs. the ICB + cRT group, and the ICB + sRT group vs. the ICB + cRT group. The caliper width was set at 0.2 standard deviations, with no replacement applied. The study’s propensity score incorporated the following variables: time since radiotherapy, DT, tumor type, gender, age, KPS score, smoking status, alcohol consumption, BMI, coronary artery disease (CAD), hypertension, diabetes, T stage, N stage, M stage, and target drug. Pearson’s chi-square test (or Fisher’s exact test for sparse data) was used to compare categorical variables between the two groups. Multiple comparisons were corrected using the Bonferroni-Holm correction. The effect size (such as r value), power (80%), and significance level (α = 0.05) used to determine the required sample size. Independent samples t tests or Wilcoxon rank-sum tests (depending on distributional assumptions) were used to compare the differences in anxiety and depression scores between two groups. p-values were adjusted using the Holm-Bonferroni correction (Holm, 1979). The steps for the power analysis are as follows: convert the effect size r value to the corresponding Z-value, calculate the noncentrality parameter by incorporating the sample size and significance level, and then back-calculate the power. Quantitative data with a normal distribution are shown as the means ± SDs; if not normally distributed, they are represented as medians (Q1, Q3). The date were analyzed using SPSS (v26.0) and R software (v4.2.3). Graphs were created using GraphPad Prism (v10.1.2). P <0.05 was considered statistically significant.

This is the first study to explore the effect of combined ICB on depression and anxiety in stage III–IV HNC patients after RT. We found that HNC patients receiving CRT combined with ICB, both concurrent RT and sequential RT, had lower depression levels than did patients receiving CRT alone. As previously mentioned, two studies have reported the negative roles of anxiety and depression in the efficacy of ICB. It looks like a closed loop (graphical abstract) (9, 10). There is currently no direct evidence to explain this result. It has previously been proposed that increased depression is independently linked to worsened neurocognition among primary brain tumor patients receiving RT (12). For late-stage HNC patients, the target area of RT is relatively large and normal brain tissue is inevitably inevitable exposed to radiation. Clinical manifestations may include mental disorders, focal neurological deficits, and the progressive degeneration of learning and memory functions due to hippocampal damage (13–16). Therefore, one of the possible explanations might be related to the effect of PD-1/PD-L1 inhibitors on the cognitive function of patients. Alzheimer’s disease (AD) is clinically characterized by memory loss and cognitive decline (17). In AD and dementia mouse models, Baruch et al. and Rosenzweig et al. demonstrated that a PD-1/PD-L1 inhibitor evokes an IFNγ-dependent systemic immune response that recruits monocyte-derived macrophages to the brain. This immunological response can improve cognitive performance (18, 19). However, a more likely explanation is that, PD-1 inhibitors can reduce neuroinflammatory responses and may also regulate neuronal activity (19–21). Direct damage to neurons and chronic inflammation induced by RT are well recognized (22), and depressive-like behavior in vivo occurs mainly via neuroinflammatory response activation (23). It is reasonable to speculate that PD-1/PD-L1 inhibitors can also reduce the RT-induced decrease in cognitive function. However, owing to the lack of brain structure-specific dosimetry data, especially for hippocampal radiation exposure, we cannot directly assess the relationships among regional radiation doses, neuroinflammation, and changes in anxiety or depression. These findings should be further validated in HNC patients.

Additionally, although our findings revealed a statistically detectable association between radiotherapy sequencing data and HADS scores, the magnitude of these differences may not reach the threshold for meaningful clinical changes in most patients. The clinical implications of these unique findings merit further evaluation, and pretreatment mood assessment should be included to assess treatment-attributable changes in future studies. Notably, power analysis revealed that after PSM, the statistical power for some comparisons fell below 0.8, indicating that our ability to detect true differences in these cases was limited, with an increased risk of Type II error. Future studies with larger sample sizes would help strengthen the evidentiary basis and confirm the robustness of these findings.

In this study, HNC patients receiving CRT combined with ICB, both concurrent RT and sequential RT, had lower depression levels than did those receiving CRT alone. Conversely, no significant differences in anxiety levels were noted across these treatment groups. This study is the first to show that patients who received ICB tended to have lower HADS scores over time. This information may have important implications for personalized approaches to preventing anxiety or depression in HNC patients.