Neoadjuvant PD-1 Inhibitor Plus SOX Chemotherapy With or Without Short-Course Radiotherapy for Locally Advanced Upper Gastric or GEJ Adenocarcinoma

This study is a prospective, open-label, multicenter, randomized controlled clinical trial designed to enroll patients with previously untreated, resectable locally advanced adenocarcinoma of the upper stomach or gastroesophageal junction. After providing informed consent and meeting the eligibility criteria, enrolled patients will be randomized into two cohorts: Cohort 1 (experimental group) will receive sequential short-course radiotherapy (SCRT) followed by four cycles of SOX plus serplulimab as neoadjuvant therapy prior to surgery; Cohort 2 (control group) will receive four cycles of SOX plus serplulimab as neoadjuvant therapy before surgery. Postoperatively, all patients will continue with four cycles of SOX plus serplulimab as adjuvant therapy, with serplulimab maintained for one year. If patients do not meet the criteria for radical gastrectomy, alternative conservative treatments or surgical approaches will be considered following multidisciplinary team (MDT) discussion. The study aims to evaluate the efficacy and safety of SOX combined with serplulimab, and sequential SCRT followed by SOX plus serplulimab as neoadjuvant therapy leading to radical resection of gastric cancer. All enrolled patients will undergo PD-L1 expression analysis (CPS and TPS scores) and microsatellite instability status (MSI-H population). Where tissue availability and research center conditions permit, exploratory assessments will include minimal residual disease (MRD) measured at baseline, after neoadjuvant therapy, post-surgery, and after adjuvant therapy, tumor mutational burden (TMB), and whole-exome sequencing of tumor tissue. Radiological evaluations will be conducted every 3 months ± 1 week for the first 2 years post-surgery, then every 6 months ± 2 weeks up to 5 years, and annually thereafter until disease recurrence. Survival follow-up will occur every three months after recurrence. Safety visits will span from the first dose to 30 days after the last dose or initiation of n