Emotional distress is associated with neuroendocrine-immune remodeling and less favorable neoadjuvant immunotherapy outcomes in oral squamous cell carcinoma.

Background: Immunotherapy research, particularly in the neoadjuvant setting, has largely focused on tumor-intrinsic determinants, with limited attention to host-related factors. Emotional distress (ED), a prevalent condition in cancer patients, remains poorly understood in the context of neoadjuvant immunotherapy (NAIT). Methods: We analyzed a cohort of 68 patients with locally advanced OSCC treated with NAIT. ED was assessed using the EORTC QLQ-C30 to stratify patients, and clinical outcomes were evaluated to determine therapeutic efficacy. Serum neuroendocrine markers were measured to assess neuroendocrine activation. Integrated single-cell, spatial, and multiplexed imaging approaches were employed to characterize immune remodeling and macrophage-Treg interactions. A chronic restraint stress mouse model was established to investigate stress-associated tumor immune remodeling and therapeutic response during anti-PD-1 therapy. Results: Elevated ED was associated with a lower disease control rate and inferior event-free survival. High-distress patients exhibited increased serum cortisol levels, which were associated with less favorable treatment outcomes. Multi-omics analyses suggested an immunosuppressive tumor microenvironment in distressed patients, characterized by regulatory T cell enrichment and increased macrophage-Treg spatial association within organized niches. Conclusions: Emotional distress may represent a clinically relevant and potentially modifiable host-related factor associated with NAIT outcomes in OSCC. Stress-associated glucocorticoid signaling may contribute to immunosuppressive tumor remodeling and less favorable therapeutic response. These findings provide a rationale for integrating psychosocial assessment and neuroendocrine-targeted interventions into perioperative immunotherapy strategies.