Associations of a Pre-Chemotherapy Anxiety-Sleep Disturbance Phenotype with Cellular Immunity and Quality of Life in Colorectal Cancer Patients: Statistical Mediation by Cortisol and IL-6.

BACKGROUND: Neuroimmunomodulation examines nervous-immune interactions via hormonal and inflammatory pathways. This study investigated whether the anxiety-sleep disturbance symptom cluster in colorectal cancer (CRC) patients undergoing chemotherapy is associated with neuroendocrine dysregulation, cellular immune alterations, and quality of life (QoL), and tested whether cortisol and interleukin-6 (IL-6) act as biological mediators. METHODS: In this prospective baseline observational study, 268 CRC patients scheduled to initiate systemic chemotherapy were assessed within 24 hours before their first chemotherapy cycle. Anxiety (HADS-A), sleep quality (PSQI), and QoL (EORTC QLQ-C30) were assessed. Serum cortisol, IL-6, and TNF-α were quantified by ELISA. Lymphocyte subsets (CD3+, CD4+, CD8+, NK cells) and regulatory T cells (Tregs) were analyzed by flow cytometry. Patients with HADS-A ≥8 and PSQI >5 formed the Symptom Cluster group (n=118), while the remaining patients constituted the Non-cluster comparator group (n=150). Mediation analysis using bootstrapping tested cortisol and IL-6 as intermediaries. RESULTS: The Symptom Cluster group showed significantly elevated cortisol, IL-6, and TNF-α (all P<0.001), higher Treg proportion (8.4% vs. 4.6%, P<0.001), and lower CD3+, CD4+, and NK cell counts (all P<0.001). Global QoL was reduced (36.4 vs. 69.5, P<0.001). Cross-sectional mediation models indicated that the association between symptom-cluster status and CD4+ T-cell count was statistically mediated by cortisol (indirect effect, -117.45; 95% bootstrap CI, -168.22 to -75.40), and the association with global QoL was statistically mediated by IL-6 (indirect effect, -13.85; 95% bootstrap CI, -18.50 to -9.80), accounting for 37.9% and 41.8% of the total effects, respectively. CONCLUSION: The anxiety-sleep disturbance symptom cluster in CRC chemotherapy patients is associated with neuroendocrine-inflammatory dysregulation, effector immune suppression, Treg expansion, and impaired QoL. Exploratory mediation findings suggest that cortisol and IL-6 may be involved in statistical indirect associations between this pre-chemotherapy anxiety-sleep disturbance phenotype and immune/QoL outcomes; longitudinal studies are needed to determine temporal and causal relationships.