Inclusion Criteria:
Participants must meet all of the following criteria:
1. Histologically and/or cytologically confirmed diagnosis of locally advanced gastroesophageal junction adenocarcinoma (GEJA), Siewert type I-III, with staging of cT3-4, any N, M0 or cT2 N+, M0, according to the AJCC 8th edition.
2. Resectable locally advanced disease as determined by multidisciplinary team (MDT) assessment.
3. Age ≥18 years, regardless of sex.
4. ECOG performance status of 0 or 1.
5. Estimated life expectancy of ≥3 months.
6. No prior anti-tumor therapy.
7. At least one measurable lesion per RECIST v1.1, defined as:
* Lesion ≥1 cm in longest diameter on spiral CT, or
* Lesion ≥2 cm in longest diameter on conventional CT or MRI.
* Imaging must be performed within 28 days prior to enrollment.
8. Adequate organ function within 14 days prior to treatment, as defined below (Note: No RBC or platelet transfusion or use of G-CSF within 14 days prior to hematology testing):
Hematologic:
* Hemoglobin ≥9 g/dL (without transfusion)
* ANC ≥1.5 × 10⁹/L
* WBC ≥3.0 × 10⁹/L (without G-CSF)
* Platelets ≥75 × 10⁹/L (without IL-11 or TPO)
Biochemical:
* Total bilirubin ≤1.5 × ULN
* AST and ALT ≤2.5 × ULN
* Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (Cockcroft-Gault formula)
* Albumin ≥25 g/L (2.5 g/dL)
Coagulation (within 7 days prior to enrollment):
* INR \<1.5
* APTT \<1.5 × ULN
* INR or PT ≤1.5 × ULN
9. For patients with active hepatitis B or C:
* Antiviral therapy must be initiated ≥14 days before enrollment
* HBV DNA ≤500 IU/mL or ≤2500 copies/mL; HCV RNA undetectable
* Must agree to continue antiviral therapy during the study
10. Left ventricular ejection fraction (LVEF) ≥50% by echocardiography.
11. Women of childbearing potential:
* Negative serum or urine pregnancy test within 7 days prior to enrollment
* Agree to use effective contraception during the study and for at least 3 months after the last dose
* Must not breastfeed or donate/retrieve ova within 60 days after the last dose
* Effective contraception must be continued for at least 6 months after last dose of chemotherapy
12. Men must be surgically sterile or agree to use effective contraception during the study and for at least 3 months after the last dose.
13. Voluntarily signed informed consent with good compliance and willingness to complete study procedures and follow-up.
Exclusion Criteria:
Participants who meet any of the following conditions will be excluded:
1. Diagnosed as mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) by immunohistochemistry or gene testing.
2. Evidence of peritoneal or multi-organ metastatic disease, as confirmed by chest and abdominal CT, bone scan, or MRI (in cases with suspected osseous lesions).
3. History of or concurrent other malignancies within the past 5 years, excluding cured basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
4. Known allergy to any component of the investigational drugs, history of severe hypersensitivity, or any contraindication to study drugs.
5. Clinically significant upper gastrointestinal bleeding within 30 days prior to enrollment or randomization.
6. History of congenital pulmonary fibrosis, drug-induced pneumonitis, active pulmonary tuberculosis, or CT-confirmed active pneumonia; interstitial lung disease requiring steroid treatment.
7. Active autoimmune or inflammatory diseases requiring immunosuppressive therapy within 2 years prior to treatment, including but not limited to:
* Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, diverticulitis),
* Systemic lupus erythematosus,
* Sarcoidosis,
* Tuberculosis,
* Wegener's granulomatosis,
* Myasthenia gravis,
* Graves' disease,
* Rheumatoid arthritis,
* Hypophysitis,
* Uveitis,
* Glomerulonephritis,
* Nephrotic syndrome,
* Fanconi syndrome, or renal tubular acidosis. Exceptions: type 1 diabetes, hypothyroidism controlled by hormone replacement, and non-systemically treated dermatologic conditions (e.g., vitiligo, psoriasis, alopecia).
8. History of immunodeficiency, HIV infection (positive HIV 1/2 antibodies), congenital or acquired immunodeficiency disorders, or history of organ transplantation.
9. Active hepatitis B (HBsAg positive) or active hepatitis C infection. Patients with past or controlled HBV/HCV infection may be eligible.
10. Use of systemic corticosteroids or immunosuppressants within 2 weeks prior to study treatment.
* Inhaled or topical corticosteroids and adrenal replacement doses (equivalent to ≤10 mg/day prednisone) are permitted.
* Short-term (\<7 days) corticosteroids are allowed for non-autoimmune conditions or prophylaxis (e.g., contrast allergy).
11. Uncontrolled or serious comorbidities, including:
* Poorly controlled hypertension (SBP ≥150 mmHg or DBP ≥100 mmHg despite medication)
* Myocardial infarction, ischemia (grade II or above), acute coronary syndrome within 6 months, arrhythmia (e.g., QTc ≥480 ms, atrial fibrillation), or uncontrolled angina
* NYHA class III-IV heart failure, LVEF \<50%, severe valvular disease, cardiomyopathy of any cause
* History of stroke or transient ischemic attack within screening period
* Active or uncontrolled infection
* Severe liver disease (e.g., cirrhosis, decompensated liver disease, chronic active hepatitis) affecting tolerability to treatment
* Poorly controlled diabetes (fasting glucose \>10 mmol/L)
* Proteinuria ≥++ on dipstick or \>1.0 g/24 h on urine protein quantification
12. Coagulation disorders (INR \>1.5 or APTT \>1.5 × ULN), bleeding tendency, or current use of thrombolytics or anticoagulants.
* Known hereditary or acquired bleeding/thrombotic conditions (e.g., hemophilia, coagulopathy, thrombocytopenia, hypersplenism).
* History of significant hemoptysis (≥2.5 mL/day) or massive bleeding within 2 months.
* Gastrointestinal bleeding, bleeding gastric ulcer, positive fecal occult blood (++ or above), vasculitis, or active bleeding within 3 months.
* Long-term use of warfarin/heparin or high-dose antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day).
13. Major surgery (e.g., craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose, or planned major surgery during the study period.
14. Gastrointestinal perforation and/or fistula within 6 months prior to enrollment; history of arterial/venous thrombotic events such as stroke (excluding clinically stable infarction per investigator), deep vein thrombosis, or pulmonary embolism.
15. Unhealed wounds or fractures of clinical significance.
16. Severe gastrointestinal conditions that may impair oral medication absorption (e.g., dysphagia, chronic diarrhea, intestinal obstruction).
17. Severe malnutrition.
18. Pregnant or breastfeeding women, or subjects (male or female within one year of menopause) unwilling to use effective contraception.
19. History of substance abuse or uncontrolled psychiatric disorders.
20. Unwilling or unable to comply with study procedures.
21. Participation in another interventional clinical trial within 30 days prior to first dose or planning to do so during the current study.
22. Any other condition deemed by the investigator to pose significant risk to patient safety or interfere with study conduct.
