This is a prospective, phase II, exploratory clinical trial. The study aims to evaluate the efficacy and safety of Retlirafusp alfa Injection in combination with chemotherapy during the perioperative period for the treatment of adenocarcinoma of the gastroesophageal junction.

A perioperative regimen comprising 3 cycles of neoadjuvant therapy → surgery → postoperative stratified maintenance therapy was employed, specifically: Retlirafusp alfa Injection (30 mg/kg, intravenous injection, D1) combined with capecitabine (1000 mg/m², oral, twice daily, D1-14) + oxaliplatin (130 mg/m², IV, D1) every 3 weeks for 3 cycles, followed by surgery; Postoperatively stratified by Tumor Regression Grade (TRG): TRG 2-4 patients receive Retlirafusp alfa Injection maintenance therapy until disease progression or intolerance (maximum duration not exceeding 1 year); TRG 1/5 patients undergo postoperative observation only.

**Inclusion Criteria:**

• Patients voluntarily enrolled in this study and signed informed consent forms;

• Aged 18-75 years, no gender restrictions;

• Histopathologically confirmed adenocarcinoma of the gastroesophageal junction with CPS > 5 and HER2-negative status;

• Clinical stage T3-4aNxM0 gastroesophageal junction adenocarcinoma (AJCC/UICC 8th Edition cTNM staging for esophageal/esophagogastric junction cancer); 5. Clinically determined resectable Siewert Type I or Siewert Type II locally advanced gastroesophageal junction adenocarcinoma;

• At least one measurable lesion present, with spiraled CT scan feasible for efficacy assessment;

• No prior anticancer therapy;

• ECOG performance status: 0-1;

• Adequate major organ function meeting the following criteria (no blood components or cell growth factors administered within 14 days prior to randomization):

  1. Neutrophils ≥ 1.5 × 10⁹/L; platelets ≥ 80 × 10⁹/L; hemoglobin ≥ 9 g/dL; serum albumin ≥ 3 g/dL;
  2. Total bilirubin ≤ 1.5 times upper limit of normal (biliary drainage permitted for biliary obstruction); ALT and AST ≤ 3 times upper limit of normal;
  3. Serum creatinine ≤ 1.5 times the upper limit of normal, creatinine clearance ≥ 50 mL/min;
  4. INR ≤ 1.5 times the upper limit of normal and APTT ≤ 1.5 times the upper limit of normal (patients on stable anticoagulant therapy such as low molecular weight heparin or warfarin with INR within the therapeutic range may be included in screening); (5) Electrocardiogram: QTcF ≤ 450 milliseconds (males), ≤ 470 milliseconds (females);

  (6) Cardiac ultrasound: Left ventricular ejection fraction (LVEF) ≥ 60%;

• For patients with active hepatitis B virus (HBV) infection: HBV DNA must be <500 IU/mL (if the study site only has copy/mL units, then <2500 copies/mL), and must have received at least 14 days of anti-HBV therapy (based on local standard treatment, e.g., entecavir) prior to study treatment initiation, with willingness to continue antiviral therapy throughout the study period; Patients with hepatitis C virus (HCV) RNA positivity must receive antiviral therapy according to local standard treatment guidelines, with liver function within the range of CTCAE Grade 1 elevation;

• Women of childbearing potential must have a negative blood pregnancy test within 3 days prior to randomization and agree to use effective contraception during the trial and for 6 months after treatment completion. Men must be surgically sterilized or agree to use effective contraception during the study and for 3 months after treatment completion.

**Exclusion Criteria:**

• Pregnant or lactating patients;

• Patients who have received prior antitumor therapy, including chemotherapy, radiotherapy, targeted therapy, or immunotherapy;

• Patients with other malignancies within the past 5 years (excluding basal cell carcinoma, superficial bladder cancer, cervical carcinoma in situ, or breast cancer);

• Uncontrolled pleural effusion, pericardial effusion, or ascites;

• Clinically determined to be inoperable or with distant metastasis;

• Severe cardiovascular disease within 12 months prior to enrollment, such as symptomatic coronary artery disease, congestive heart failure ≥ Grade II, uncontrolled arrhythmia, myocardial infarction;

• Concurrent upper gastrointestinal obstruction/bleeding, digestive dysfunction, or malabsorption syndrome;

• History of gastrointestinal perforation within 6 months prior to enrollment;

• Concurrent severe uncontrolled infections or other severe uncontrolled comorbidities, moderate or severe renal impairment;

• Uncontrolled cardiac clinical symptoms or conditions, such as:

  1. NYHA Class II or higher heart failure (see Appendix 5) or echocardiography showing LVEF <50%;
  2. Unstable angina;
  3. Myocardial infarction within 1 year prior to study treatment initiation;
  4. Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention; (5) QTc > 450 ms (males); QTc > 470 ms (females) (QTc interval calculated using Fridericia's formula; if QTc is abnormal, measure three consecutive times at 2-minute intervals and take the average);

• History of allergic reactions to drugs used in this study;

• Use of immunosuppressive drugs within 4 weeks prior to the first dose of study treatment, excluding intranasal, inhaled, or other locally administered corticosteroids, or physiologically dosed systemic corticosteroids (i.e., not exceeding 10 mg/day of prednisone or equivalent doses of other corticosteroids), or corticosteroids used for contrast medium allergy prophylaxis;

• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;

• Current interstitial pneumonia or interstitial lung disease, or prior history of interstitial pneumonia or interstitial lung disease requiring corticosteroid therapy, or other pulmonary conditions that may interfere with the assessment and management of immune-related pulmonary toxicity, such as pulmonary fibrosis, organizing pneumonia (e.g., obliterative bronchiolitis), pneumoconiosis, drug-induced pneumonia, idiopathic pneumonia, or evidence of active pneumonia on screening chest computed tomography (CT) or severe pulmonary impairment. Radiation pneumonitis in the radiation field is permitted. Active tuberculosis.

• Active autoimmune disease or history of autoimmune disease with potential for recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [subjects controllable only with hormone replacement therapy may be included]); Subjects with skin conditions not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia), controlled type 1 diabetes managed with insulin, or childhood asthma in complete remission requiring no adult intervention may be included; asthma patients requiring bronchodilator medical intervention are excluded;

• Use of immunosuppressive agents or systemic corticosteroids for immunosuppression within 14 days prior to study treatment initiation (dose > 10 mg/day prednisone or equivalent);

• Severe infection within 4 weeks prior to study treatment initiation, including but not limited to hospitalization due to infection, bacteremia, or severe pneumonia complications; therapeutic antibiotic administration (oral or intravenous) within 2 weeks prior to study treatment initiation (patients receiving prophylactic antibiotics, e.g., for urinary tract infection prevention or chronic obstructive pulmonary disease exacerbation prevention, are eligible);

• Patients with congenital or acquired immunodeficiency (e.g., HIV infection);

• Use of immunosuppressive drugs within 4 weeks prior to first dose;

• Administration of live attenuated vaccines within 4 weeks prior to first dose or planned administration of live attenuated vaccines during the study period;

• Previous treatment with other anti-PD-1 antibodies or other PD-1/PD-L1-targeted immunotherapies;

• Palliative radiotherapy to non-target lesions for symptom control is permitted, provided it was completed at least 2 weeks prior to study treatment initiation and radiotherapy-related adverse events have not recovered to ≤CTCAE Grade 1;

• Receipt of other investigational drug treatment within 28 days prior to study treatment initiation; The investigator determined that the patient has other factors that may affect study outcomes or necessitate premature termination of this study, such as alcohol abuse, substance misuse, other serious medical conditions (including psychiatric disorders) requiring concomitant treatment, severe laboratory abnormalities, or accompanying family or social factors that could compromise patient safety.