Pretreatment emotional distress and peripheral biomarkers predict immune checkpoint inhibitor response in people with advanced inoperable gastroesophageal cancer

BACKGROUND: Emotional distress (ED) has been demonstrated to compromise immune responses against tumors; however, few clinical studies have explored its influence on the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients, especially those with gastroesophageal cancer (GEC). Additionally, reliable biomarkers for predicting the response to immunotherapy remain elusive. This study was aimed at investigating whether ED affects the outcomes of immunotherapy in advanced GEC patients and identifying potential biomarkers predictive of immunotherapy efficacy. METHODS: This prospective observational cohort study enrolled 84 patients with advanced, treatment-naïve, and inoperable GEC. ED was evaluated at baseline using the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder 7-item Scale. The primary endpoint was Progression-Free Survival (PFS), while the secondary endpoint was Disease Control Rate (DCR). RESULTS: Patients with baseline ED exhibit significantly shorter median PFS (7.8 months vs. 14.0 months, HR = 2.59, 95% CI: 1.35-4.97, P = 0.004) and a lower DCR (39.5% vs. 68.3%, OR = 3.21, 95% CI: 1.29-7.98, P = 0.012) compared to those without ED. Exploratory analyses further demonstrate that both pre- and post-treatment peripheral inflammatory markers (PIMs) are independently and jointly associated with survival outcomes in combination with ED. CONCLUSIONS: This prospective study demonstrates that ED and elevated PIMs significantly impair ICI efficacy in advanced GEC. The synergistic interaction between ED and PIMs suggests underlying psycho-inflammatory mechanisms affecting treatment outcomes. These findings establish the clinical importance of integrating routine psychological assessment and PIMs monitoring in cancer patients receiving immunotherapy.