Total Neoadjuvant Immunotherapy Plus Chemotherapy for Locally Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (TNICE-1)

Inclusion Criteria:

• Able to understand the study and provide signed informed consent (ICF)
• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction, clinically staged as stage II/III disease (cT1-2N+M0 or cT3-4aNxM0) based on contrast-enhanced CT/MRI
• Willing to provide archived tumor tissue or undergo biopsy for central laboratory testing of PD-L1, EBV, and MSI/dMMR status
• Tumor with PD-L1 CPS >=5, or MSI-H/dMMR, or EBV positivity
• Male or female, age >=18 years
• ECOG performance status 0-1, with no surgical contraindications
• Life expectancy >=6 months
• Laboratory values within 7 days prior to enrollment: absolute neutrophil count (ANC) >=1.5 x 10^9/L; platelet count >=100 x 10^9/L; hemoglobin >=90 g/L; serum albumin >=30 g/L; total bilirubin <=1.5 x ULN; AST and ALT <=2.5 x ULN (<=5 x ULN in subjects with liver metastases); creatinine <=1.5 x ULN or creatinine clearance >=50 mL/min; INR and aPTT <=1.5 x ULN (applicable only to subjects not receiving anticoagulant therapy; subjects receiving anticoagulants must be on a stable dose)
• Good compliance and willingness to cooperate with protocol-required examinations and specimen collection (tissue, blood, stool, and saliva samples)
• Women of childbearing potential must agree to use contraception from the time of ICF signing until at least 5 months after the last dose of study treatment or accompanying chemotherapy, and must not breastfeed; men must agree to use contraception from the first dose of study drug until at least 7 months after the last dose

Exclusion Criteria:

• Known allergy to serplulimab or its excipients, oxaliplatin, or components of tegafur/gimeracil/oteracil potassium (S-1)
• Prior or concurrent other malignancy (except adequately treated basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix)
• Uncontrolled pericardial effusion, pleural effusion, ascites, or gastrointestinal bleeding within 2 weeks prior to enrollment
• Body weight loss >20% within 2 weeks prior to enrollment
• Unable to take oral medications
• Prior chemotherapy, radiotherapy, targeted therapy, immunotherapy, or surgery for gastric cancer
• Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibodies
• HER2-positive tumor confirmed by central laboratory testing (IHC 3+, or IHC 2+ with positive FISH/ISH)
• Comorbidities requiring long-term immunosuppressive therapy, or systemic or local corticosteroids at immunosuppressive doses
• Vaccination with any anti-infectious vaccine within 4 weeks prior to enrollment
• Uncontrolled diabetes mellitus, hypertension, or other systemic diseases
• Currently receiving or requiring anticoagulant therapy (low-dose aspirin antiplatelet therapy allowed)
• Any active autoimmune disease or history of autoimmune disease
• Active tuberculosis, currently receiving anti-tuberculosis treatment, or anti-tuberculosis treatment within 1 year prior to screening
• Confirmed interstitial pneumonitis, non-infectious pneumonitis, pulmonary fibrosis, or history of acute lung disease
• Any contraindication to oxaliplatin or S-1
• Pregnant or breastfeeding women
• Active hepatitis (HBV DNA >=10^4 copies/mL or positive HCV RNA)
• Positive HIV antibody or human T-lymphotropic virus type 1 (HTLV-1) antibody
• Any other clinically significant disease or condition that, in the investigator's judgment, may affect protocol compliance or render the subject unsuitable for participation