This study aims to evaluate the effectiveness and safety of a preoperative treatment (called neoadjuvant therapy) combining four drugs-nab-paclitaxel, oxaliplatin, S-1, and sintilimab-for patients with locally advanced, resectable early-onset gastric cancer (diagnosed at age 45 or younger).

All participants will receive this drug combination before undergoing surgery to remove the tumor. The goal is to shrink the tumor, increase the chance of complete surgical removal, and improve long-term outcomes.

This is a single-arm, open-label, phase II clinical trial, meaning all participants will receive the same treatment, and both doctors and patients will know what drugs are being used. The study is being conducted at Peking University People's Hospital.

Inclusion Criteria:

• Participants must meet all of the following inclusion criteria:
• Male or female, aged ≥16 and ≤45 years;
• Karnofsky performance score ≥70% or ECOG performance status 0-1;
• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (GEJ).
• For gastric body cancer: clinical stage cT3-T4a N+ M0;
• For GEJ cancer: clinical stage cT2-T4a N+ M0;
• For cT4b Nany M0 cases: location may be gastric body or GEJ.
• Staging is based on contrast-enhanced CT, MRI (if needed), and endoscopic ultrasonography (EUS) (if needed);
• Assessed as resectable after multidisciplinary team (MDT) discussion;
• Surgical evaluation confirms that D2 radical gastrectomy is feasible;
• Sufficient physical condition and organ function to tolerate major abdominal surgery;
• Baseline laboratory tests meet the following criteria:
• Hemoglobin ≥90 g/L
• Absolute neutrophil count (ANC) ≥1.5×10⁹/L
• Platelets ≥100×10⁹/L
• ALT and AST ≤2.5× upper limit of normal (ULN)
• Alkaline phosphatase (ALP) ≤2.5× ULN
• Total bilirubin <1.5× ULN
• Serum creatinine <1× ULN
• Serum albumin ≥30 g/L
• No severe comorbidities that may limit life expectancy to <3 years;
• Participant is willing and able to comply with the study protocol during the study period;
• Written informed consent must be signed before screening. Participants must understand their right to withdraw at any time without any loss of benefits;
• Willing to provide blood and tissue samples.

Exclusion Criteria:

• Participants meeting any of the following criteria will be excluded:
• Patients with HER-2 positive gastric cancer, as determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH);
• Patients with dMMR (deficient mismatch repair) or MSI-H (microsatellite instability-high) tumors, as determined by IHC;
• Pregnant or breastfeeding women;
• Prior treatment for gastric cancer with cytotoxic chemotherapy, radiotherapy, or immunotherapy;
• History of other malignancies within the past 5 years;
• Active autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis;
• Active inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis;
• Currently receiving systemic corticosteroids or other immunosuppressive therapy;
• Prior organ transplantation or use of anti-rejection medications;
• Active tuberculosis, HIV infection, or severe active hepatitis B or C;
• History of uncontrolled epilepsy, central nervous system disorders, or psychiatric illnesses that, in the investigator's judgment, may interfere with informed consent or compliance with oral medication;
• Clinically significant (active) cardiac diseases, including symptomatic coronary artery disease, NYHA class II or above congestive heart failure , severe arrhythmias requiring medical intervention, or myocardial infarction within the past 12 months;
• Presence of upper gastrointestinal obstruction that may impair the oral intake or absorption of S-1;
• Severe uncontrolled recurrent infections or other uncontrolled serious comorbidities;
• Use of any investigational drugs within 4 weeks prior to study enrollment.

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices), will be shared with researchers who provide a methodologically sound proposal.

IPD will be available beginning 6 months after publication and ending 5 years after publication.

Researchers requesting data sharing should send their research proposals to xuesongzhao@bjmu.edu.cn. Access to the data will require consultation with the principal investigator and the signing of a data use agreement.