Inclusion Criteria:
1. Voluntary signed informed consent and willingness to comply with protocol requirements.
2. Age ≥18 years at the time of informed consent signing; both sexes eligible.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 within 7 days before study drug administration.
4. Resectable locally advanced esophageal or gastric adenocarcinoma, as determined by the investigator, staged as cT1b-2 N+ M0 or cT3-4 Nany M0 (AJCC 8th edition).
Note: Bone scan is required if bone lesions are suspected; diagnostic laparoscopy is required if peritoneal metastasis is suspected or for Lauren diffuse-type tumors.
5\. HER2 intermediate-to-high expression by immunohistochemistry (IHC) 2+ or 3+. 6. No prior antitumor therapy for esophageal or gastric adenocarcinoma. 7. Availability of tumor tissue (primary tumor or metastatic lymph node) for pathological testing, including paraffin block, paraffin-embedded sections, or fresh tissue sections; archival tissue is preferred. If unavailable, a new baseline biopsy is required.
8\. No severe cardiac dysfunction; left ventricular ejection fraction (left ventricular ejection fraction, LVEF) ≥55% within 28 days before study drug administration.
9\. Adequate organ function within 7 days before study drug administration, defined as:
1. Hematologic function:
Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L Platelet count ≥100 × 10⁹/L Hemoglobin ≥90 g/L No blood or component transfusion within 14 days before the first dose, and no treatment with hematopoietic growth factors (e.g., granulocyte colony-stimulating factor (G-CSF) , erythropoietin) within 7 days before the first dose.
2. Hepatic function:
Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
3. Renal function:
Serum creatinine (Cr) ≤1.5 × ULN, or creatinine clearance (CrCl) ≥50 mL/min (calculated by the Cockcroft-Gault formula).
4. Coagulation function:
International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (APTT) ≤1.5 × ULN (except for patients receiving therapeutic anticoagulation).
5. Urinalysis:
Urine protein \<2+; if urine protein ≥2+, 24-hour urine protein must be ≤1 g. 10. Male participants and women of childbearing potential (including premenopausal women and women within 2 years after menopause) must agree to use effective contraception from the time of informed consent signing until 6 months after the last dose of study drug. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose of study drug.
Exclusion Criteria:
1. Pathological diagnosis of HER2-negative esophageal or gastric adenocarcinoma, defined as HER2 IHC 0 or 1+.
2. Presence of contraindications to esophageal or gastric surgical resection.
3. History of another primary malignancy, except for: basal cell carcinoma of the skin, superficial bladder cancer (Ta, non-invasive), squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; or malignancies that have received curative treatment and remained recurrence-free for ≥5 years.
4. Presence of non-regional lymph node or distant organ metastasis. For suspected peritoneal carcinomatosis or ascites on imaging, histological or cytological confirmation via laparoscopy or other procedures is required.
5. Significant clinically meaningful bleeding or definite bleeding tendency within 1 month before informed consent, such as gastrointestinal bleeding or fecal occult blood ≥2+ (positive); or endoscopically, radiologically, or highly suspected esophageal fistula or gastric perforation.
6. Any serious or uncontrolled systemic disease at the discretion of the investigator, including uncontrolled hypertension (systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg), uncontrolled diabetes mellitus, or signs of active bleeding.
7. Serious cardiovascular or cerebrovascular disease, including but not limited to: NYHA class II or greater heart failure; myocardial infarction or cerebrovascular accident (cerebral ischemia, symptomatic cerebral infarction, etc.) within 3 months before the first dose; grade ≥2 persistent arrhythmia (per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ); atrial fibrillation of any grade; unstable arrhythmia or unstable angina within 1 month before the first dose in patients with coronary artery disease; congestive heart failure not meeting the above criteria; or symptomatic superior vena cava syndrome.
8. Evidence of active infection, including hepatitis B (HBsAg positive with HBV DNA ≥2000 IU/mL, after excluding drug-induced or other causes of hepatitis), hepatitis C (anti-HCV antibody positive with HCV RNA above the lower limit of detection), or human immunodeficiency virus (HIV) infection; or uncontrolled active bacterial, viral, fungal, rickettsial, or parasitic infection unless treated and resolved before study drug administration.
9. History of hypersensitivity to any component of the study drugs, or history of grade ≥3 hypersensitivity to macromolecular protein preparations or monoclonal antibodies.
10. History of primary immunodeficiency or active autoimmune disease; or current use of immunosuppressants or systemic corticosteroids (≥10 mg/day prednisone or equivalent) that continued within 2 weeks before enrollment.
Note: Patients with type 1 diabetes mellitus, stable hypothyroidism on hormone replacement therapy (including hypothyroidism due to autoimmune thyroid disease), psoriasis not requiring systemic treatment, or vitiligo are eligible.
11. History of interstitial pneumonia, radiation pneumonitis, severe chronic obstructive pulmonary disease, severe pulmonary dysfunction, or symptomatic bronchospasm.
12. Breastfeeding women unwilling to use adequate contraception during the study and for 6 months after the last dose of study drug.
13. Any other condition that, in the opinion of the investigator, makes the participant unsuitable for enrollment in this clinical trial.
