Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
- Voluntary participation in the study, with written informed consent, and willingness and ability to comply with the study treatment and follow-up requirements.
- Male or female participants aged 18 to 75 years.
- Histologically or cytologically confirmed gastric or gastroesophageal junction adenocarcinoma.Resectable locally advanced disease as determined by imaging assessment or a multidisciplinary team according to the eighth edition of the American Joint Committee on Cancer staging system, generally defined as cT3-4a with any N category, or any T category with node-positive disease, corresponding to stage II-III disease, without distant metastasis.
- Eastern Cooperative Oncology Group performance status of 0 or 1.
- Acceptable cardiopulmonary function, including all of the following:
(1)No clinically significant abnormality on electrocardiography; (2)Resting heart rate of at least 60 beats per minute; (3)Systolic blood pressure of at least 90 mmHg; (4)No progressive or decompensated cardiopulmonary disease; (5)Left ventricular ejection fraction of at least 50%. 6.Adequate organ function during screening, defined as follows:
- Absolute neutrophil count of at least 1.5 × 10⁹/L;
- Platelet count of at least 75 × 10⁹/L;
- Hemoglobin level of at least 90 g/L;
- Total bilirubin no greater than 1.5 times the upper limit of normal;
- Aspartate aminotransferase and alanine aminotransferase no greater than 2.5 times the upper limit of normal;
- Serum creatinine no greater than 1.5 times the upper limit of normal or creatinine clearance of at least 50 mL/min;
- International normalized ratio no greater than 1.5 times the upper limit of normal, unless the participant is receiving stable anticoagulation and is considered eligible by the investigator.
7.Female participants of childbearing potential must have a negative pregnancy test during screening. Male and female participants of reproductive potential must agree to use effective contraception during the study and for at least 6 months after the last dose of study treatment.
Exclusion criteria
- Distant metastatic disease confirmed by imaging or diagnostic laparoscopy, including but not limited to peritoneal, hepatic, or bone metastases, or positive peritoneal cytology.
- Previous systemic anticancer treatment for the current malignancy, including chemotherapy, immunotherapy, or targeted therapy, or previous radiotherapy. Diagnostic endoscopy and biopsy are permitted.
- Grade 2 or higher peripheral neuropathy at baseline.
- A second primary malignancy requiring systemic treatment within the previous 3 years, except for adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, low-risk thyroid cancer, or other malignancies considered cured.
- Inability to tolerate curative-intent surgery or study treatment, as determined by the investigator.
- Active autoimmune disease, or a clinically significant history of autoimmune disease requiring systemic immunosuppressive treatment within the previous 2 years. Participants with type 1 diabetes mellitus, stable thyroid disease requiring replacement therapy, vitiligo, or grade 2 or lower psoriasis not requiring systemic treatment may be eligible.
- Use of systemic corticosteroids at a prednisone-equivalent dose of at least 10 mg/day, or other systemic immunosuppressive agents, within 14 days before the planned initiation of immunotherapy. Physiologic replacement therapy, inhaled or topical corticosteroids, and short-term prophylactic treatment related to surgery are permitted.
- Active infection, including but not limited to active tuberculosis, uncontrolled hepatitis B virus or hepatitis C virus infection, human immunodeficiency virus infection, or another serious infection requiring intravenous antibiotic treatment.
- Any contraindication to propranolol, including:
(1)Bronchial asthma or a risk of bronchospasm; (2)Diabetic ketoacidosis or metabolic acidosis; (3)Severe or symptomatic bradycardia; (4)Second- or third-degree atrioventricular block, sinoatrial block, or sick sinus syndrome; (5)Cardiogenic shock; (6)Right-sided heart failure caused by pulmonary hypertension; (7)Congestive heart failure; (8)Clinically significant hypotension; (9)Prolonged fasting; (10)Severe peripheral circulatory failure; (11)Untreated pheochromocytoma; (12)Variant angina; (13)Concomitant treatment with rizatriptan benzoate. 10.Moderate or severe chronic obstructive pulmonary disease with a recent acute exacerbation.
11.Active upper gastrointestinal bleeding at baseline, melena or hematemesis within the previous 4 weeks, bleeding requiring blood transfusion or endoscopic hemostasis, uncontrolled peptic ulcer disease, or a high risk of recent bleeding as determined by the investigator.
12.Requirement for continuous full-dose anticoagulation, dual antiplatelet therapy that cannot be interrupted, or a bleeding disorder that cannot be adequately managed during the perioperative period.
13.Known hypersensitivity to propranolol, oxaliplatin, S-1 or fluoropyrimidines, toripalimab, or any of their excipients, or a history of a severe adverse reaction to any of these agents.
14.Concomitant use of medications that cannot be discontinued or replaced and that may cause clinically significant interactions with propranolol, including verapamil, diltiazem, class I or class III antiarrhythmic agents, strong CYP2D6 or CYP1A2 inhibitors, or other medications considered by the investigator to pose a major drug-drug interaction risk.
15.Uncontrolled bleeding disorder, or major surgery or serious trauma within 4 weeks before enrollment, excluding the curative-intent surgery planned as part of this study.
16.Pregnancy or breastfeeding, or unwillingness to use the required contraceptive measures.
17.Any medical, psychiatric, social, or other condition that, in the investigator's judgment, may compromise participant safety, treatment compliance, or completion of the required follow-up, including severe psychiatric illness, substance abuse, or inability to attend scheduled visits.
