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 new antitumor therapy.

Inclusion Criteria:

• The participant voluntarily joins this study, is able to complete the signing of the informed consent form, and demonstrates good compliance.
• Age 18-75 years (at the time of signing the informed consent), regardless of gender.
• Adenocarcinoma confirmed by histology and/or cytology, diagnosed as locally advanced according to the AJCC 8th edition criteria, with cTNM staged as cT3-4 or N+ M0 based on endoscopic ultrasound or contrast-enhanced CT/MRI, and the patient agrees to receive neoadjuvant therapy; the lesion is assessed by the investigator as resectable or potentially resectable; after MDT evaluation, radical resection is planned with standard D2 lymph node dissection.
• Primary lesion site restrictions: (1) Adenocarcinoma of the gastroesophageal junction: Siewert type II-III; (2) Upper stomach cancer: the lower edge of the tumor is located within the upper third of the stomach, mainly involving the cardia, fundus, or upper part of the stomach body.
• Has not previously received systemic treatment for the current disease, including anti-tumor radiotherapy/chemotherapy or immunotherapy.
• ECOG score 0-1.
• Estimated survival period >= 6 months.
• Preoperative chest, abdominal, and pelvic CT, as well as FAPI PET or PET-CT, to rule out distant metastasis.
• Major organ function is satisfactory and meets the following criteria: (1) Complete blood count (without blood transfusion or use of hematopoietic growth factors within 14 days to correct status): hemoglobin (Hb) >=90 g/L; absolute neutrophil count (ANC) >=1.5 × 10^9/L; platelets (PLT) >=80 × 10^9/L; (2) Biochemical tests: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 × ULN; total bilirubin (TBIL) <=1.5 × ULN; serum creatinine (Cr) <=1.5 × ULN, or creatinine clearance >=60 mL/min; (3) Coagulation function: activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) <=1.5 × ULN; (4) Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) >=50%.
• The doctor clinically determines that there is sufficient organ function.
• Subjects of reproductive potential must use appropriate contraception during the study and for 120 days after the study ends, have a negative serum pregnancy test within 7 days prior to study enrollment, and must not be breastfeeding.

Exclusion Criteria:

• Undergo radiotherapy within 4 weeks before enrollment, or radionuclide therapy within 8 weeks.
• Within 6 months before enrollment: esophageal or gastric varices, severe ulcers, unhealed wounds, gastrointestinal perforation, fistulas, intestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding.
• Diagnosis of malignancies other than gastric cancer within 5 years prior to first administration (excluding completely treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or completely resected carcinoma in situ).
• Presence of distant metastasis (M1), including but not limited to: peritoneal metastasis (confirmed by imaging or laparoscopy), ascites or positive peritoneal lavage cytology, metastasis to organs such as liver, lung, or bone; cases where imaging suggests metastasis to para-aortic lymph nodes (No.16).
• Imaging suggests excessive regional lymph node burden: suspicious/positive lymph node involvement in >=3 anatomical stations; or multiple lymph nodes are fused/form a cluster (matted nodes); or any lymph node has a short axis >=15 mm.
• The tumor lesion has a serious tendency to bleed (such as the presence of an active deep large ulcer, a history of vomiting blood or black stools within 2 months before signing the informed consent, or a risk of major gastrointestinal bleeding as determined by the investigator), or has received blood transfusion treatment within 4 weeks prior to the study medication.
• Inability to swallow oral medications, malabsorption syndrome, or other conditions affecting gastrointestinal absorption.
• Currently participating in interventional clinical research treatment, or has received other investigational drugs or used investigational devices within 4 weeks prior to the first administration.
• Previously received systemic or local anti-tumor treatment for gastric cancer, including curative surgery, chemotherapy, radiotherapy, immunotherapy (such as immune checkpoint inhibitors, agonists, or cell therapy), biological agents, or small molecule targeted drugs.
• Systemic therapy with traditional Chinese medicine having anti-tumor indications or immunomodulatory drugs (including thymosin, interferon, interleukins, except for local use to control pleural effusion) within 2 weeks prior to the first dose.
• Active autoimmune disease that required systemic treatment (such as disease-modifying drugs, glucocorticoids, or immunosuppressants) within 2 years before the first administration. Replacement therapies (such as thyroid hormone, insulin, or physiological glucocorticoids used for adrenal or pituitary insufficiency) are not considered systemic treatment.
• The participant is receiving systemic corticosteroid therapy (excluding nasal, inhaled, or other forms of topical corticosteroids) or any other form of immunosuppressive therapy within the 7 days prior to the first study drug administration; Note: The use of physiological doses of corticosteroids (<=10 mg/day of prednisone or equivalent) is allowed; short courses of corticosteroids are allowed for medically necessary reasons such as chemotherapy-induced nausea, premedication for contrast agent allergy, or other short-term medical needs.
• Known allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation.
• Known allergies to medications used in this study.
• Peripheral neuropathy >= grade 2.
• Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive).
• Subjects with active hepatitis B or hepatitis C (HBsAg positive with HBV DNA levels above the upper limit of normal; HCVAb positive with HCV RNA levels above the upper limit of normal (Note: Subjects who are HBV DNA positive may be enrolled if they are willing to undergo full antiviral treatment throughout the study and have already started treatment before enrollment, subject to consultation with an infectious disease specialist).
• Within 30 days before the first dose (Cycle 1, Day 1), live vaccines were administered; inactivated influenza vaccines for injection against seasonal flu are allowed within 30 days before the first dose; however, intranasal live attenuated influenza vaccines are not allowed.
• Pregnant or breastfeeding women.
• Presence of any severe or uncontrollable systemic disease, such as: (1) Significant and symptomatic abnormalities on resting electrocardiogram in rhythm, conduction, or morphology that are difficult to control, such as complete left bundle branch block, second-degree or higher heart conduction block, ventricular arrhythmias, or atrial fibrillation; (2) Unstable angina, congestive heart failure, chronic heart failure with New York Heart Association (NYHA) class >= 2; (3) Any arterial thrombosis, embolism, or ischemia within 6 months prior to treatment, such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack; (4) Long-term poorly controlled hypertension (systolic blood pressure >160 mmHg, diastolic blood pressure >100 mmHg); (5) History of non-infectious pneumonia requiring corticosteroid therapy within 1 year before initial dosing, or currently active interstitial lung disease; (6) Significant bleeding disorders or a history of coagulopathy; current or past long-term anticoagulant therapy (e.g., atrial fibrillation with CHADS2 score >=2); (7) Active pulmonary tuberculosis; (8) History of inflammatory bowel disease (such as Crohn's disease, ulcerative colitis) or chronic diarrhea; (9) Major surgery or major trauma within 30 days prior to treatment; minor local surgery within 3 days prior to treatment (excluding central venous catheter placement via peripheral vein); (10) Presence of active or uncontrolled infection requiring systemic therapy; (11) Presence of clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction; (12) Uncontrolled comorbidities including but not limited to decompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer or gastritis, or mental/social conditions that interfere with protocol compliance or informed consent; (13) Poorly controlled diabetes (fasting blood glucose (FBG) >10 mmol/L); (14) Urinalysis indicating proteinuria >=++, confirmed by 24-hour urine protein quantification >1.0 g.
• Known history of mental illness, substance abuse, alcoholism, or drug addiction.
• Any history or evidence of disease that may interfere with the trial results, hinder the subject's full participation in the study, abnormal treatment or laboratory test results, or any other condition that the investigator considers unsuitable for enrollment. The investigator believes that there are other potential risks making the subject unsuitable to participate in this study.
• Local or systemic diseases caused by tumors, or tumor-related complications with high medical risk or uncertain prognosis (for example, leukocyte response resulting in leukocytes >20 × 10^9/L, cachexia, weight loss >10% in the three months before screening), or BMI <=18).

regardless of gender;

partial data will be shared 3 years after the study was completed and end in 5 years.