In this study, the investigators will use Tislelizumab combined with LM-302 and S-1 versus Tislelizumab combined with SOX to treat Claudin 18.2-positive locally advanced gastric or gastroesophageal junction adenocarcinoma.

Inclusion Criteria:

• Patients voluntarily participate in this study and sign the informed consent form;
• Age ≥ 18 years;
• Histopathologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma;
• HER2 negative;
• Determined by contrast-enhanced CT and laparoscopy to have radically resectable disease with clinical stage T3-4 N+ M0 (according to the AJCC 8th edition);
• Claudin 18.2 positive (≥25% of tumor cells showing moderate-to-strong membrane staining);
• No prior receipt of other targeted therapies against claudin 18.2;
• ECOG performance status 0-1;
• Life expectancy ≥ 12 months;
• Adequate major organ function.

Exclusion Criteria:

• Known HER2-positive gastric cancer；

• Gastroesophageal junction (EGJ) cancer involving the proximal stomach with the tumor center located ≤2 cm from the EGJ；

• Peritoneal metastasis, positive peritoneal cytology (CY1P0), or retroperitoneal lymph node metastasis (No. 16a2/b1) or other distant metastases;

• Presence of unresectable factors, including unresectability due to tumor characteristics, surgical contraindications, or patient refusal of surgery;

• Prior or concurrent other malignancy, except for cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and carcinoma in situ of the breast;

• Presence of any of the following cardiac clinical symptoms or diseases:

  • New York Heart Association (NYHA) class ≥2 heart failure or left ventricular ejection fraction (LVEF) <50% on color Doppler echocardiography;
  • Unstable angina;
  • Resting electrocardiogram (ECG) showing QTc >450 ms (male) or QTc >470 ms (female);
  • Resting ECG showing clinically significant abnormalities (e.g., abnormalities in heart rate, conduction, morphology), complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block, or PR interval >250 ms.

• History of gastrointestinal perforation, intra-abdominal abscess, or intestinal obstruction within the past 3 months, or evidence of intestinal obstruction by imaging or clinical symptoms;

• Arterial/venous thrombotic events within 6 months before randomization, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, or pulmonary embolism;

• Known hereditary or acquired bleeding or thrombotic predisposition (e.g., hemophilia, coagulation disorders, thrombocytopenia);

• Active peptic ulcer, unhealed wound, or bone fracture;

• Active infection requiring antimicrobial therapy (e.g., antibacterial, antiviral, or antifungal treatment);

• Active hepatitis [hepatitis B: HBsAg positive and HBV DNA ≥500 IU/mL; hepatitis C: HCV antibody positive and HCV viral load > upper limit of normal]; 13. Congenital or acquired immunodeficiency (e.g., HIV-infected patients);

• Planned or prior organ or allogeneic bone marrow transplantation;

• Current interstitial pneumonia or interstitial lung disease, or a history of interstitial pneumonia/ lung disease requiring steroid therapy, or other pulmonary conditions that may interfere with the assessment and management of immune-related lung toxicity, including pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), pneumoconiosis, drug-induced pneumonitis, idiopathic pneumonitis, or active pneumonia or severe pulmonary dysfunction on screening CT scan;

• Active pulmonary tuberculosis;

• Any active autoimmune disease or history of autoimmune disease with potential for relapse [including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (patients controlled with hormone replacement therapy alone are eligible)];

• Known hypersensitivity to any study drug or excipient;

• Lactating women;

• Any other condition that, in the investigator's judgment, may affect the study results or necessitate premature termination of the study, such as alcohol or drug abuse, other serious diseases (including psychiatric disorders) requiring concomitant treatment, significant laboratory abnormalities, or family/social factors that could compromise patient safety.