Correlation of Psychological Distress and Immune Checkpoint Inhibitors in Gastric Cancer

1. Background Gastric cancer (GC) is a leading global cause of cancer-related mortality, with over 1 million new cases and 769,000 deaths in 2020. In China, 80% of patients present with advanced disease, for whom perioperative chemotherapy, surgery, and lymphadenectomy are standard. Recent phase III trials (Checkmate-649, KEYNOTE-062, ORIENT-16) demonstrate that immune checkpoint inhibitors (ICIs) combined with chemotherapy improve progression-free survival (PFS: 2.8-10.5 months) and overall survival (OS: 11.1-18.4 months) compared to chemotherapy alone. However, outcomes remain suboptimal, necessitating exploration of novel predictive biomarkers and resistance mechanisms. Emerging evidence implicates chronic stress in cancer progression and treatment response. Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, elevating cortisol, catecholamines, and glucocorticoids. These hormones suppress immune function by reducing CD8+ T cells and natural killer (NK) cell activity while increasing immunosuppressive cells (e.g., regulatory T cells, myeloid-derived suppressor cells). Preclinical studies link chronic stress to metastasis via extracellular trap (NET) formation, impaired antitumor immunity, and resistance to PD-1/PD-L1 blockade. Clinically, chronic stress correlates with worse survival in non-small-cell lung cancer patients receiving ICIs. Despite these findings, psychological screening remains underutilized in oncology. This study aims to investigate the impact of chronic stress on ICI efficacy in advanced gastric cancer. 2. Objectives Primary Objective: Evaluate the association between chronic stress and tumor response (via Tumor Regression Grade, TRG) in advanced gastric cancer patients undergoing neoadjuvant immunotherapy. Secondary Objectives: Assess the effect of chronic stress on post-gastrectomy quality of life (QoL). Analyze correlations between chronic stress biomarkers and survival