Malnutrition is highly prevalent in patients with upper gastrointestinal tumors, which may negatively impact treatment tolerance and anti-tumor immune responses. This study aims to evaluate the efficacy and safety of intensive enteral nutritional support in patients with locally advanced unresectable esophageal squamous cell carcinoma (ESCC) undergoing conversion therapy. Participants receiving PD-1 inhibitors combined with chemotherapy will be randomly assigned to either intensive nutritional support or standard care. The primary goal is to determine if intensive nutritional support can improve the pathological complete response (pCR) rate after subsequent surgery.

Inclusion Criteria:

Pathologically confirmed Esophageal Squamous Cell Carcinoma (ESCC). Aged 18-80 years, regardless of gender. ECOG Performance Status (PS) 0-2, and weight loss < 10% within the past 6 months.

Confirmed locally advanced unresectable ESCC according to NCCN Guidelines (Version 2026.1).

Planned to receive surgery after completion of conversion therapy, with no surgical contraindications.

Treatment-naive: No prior anti-tumor therapy for ESCC, including radiotherapy, chemotherapy, or surgery.

Presence of measurable lesion(s) according to RECIST 1.1. Expected survival ≥ 3 months. Able to swallow and tolerate oral medications. Adequate organ function (blood counts, biochemistry, and coagulation parameters meeting protocol requirements).

Women of childbearing age and men must agree to use effective contraception during the study and for 6 months after completion.

Voluntary participation with signed informed consent and good compliance.

Exclusion Criteria:

Presence of esophageal-mediastinal fistula and/or tracheoesophageal fistula, or tumor invasion of major vessels with risk of fatal hemorrhage.

History of other malignant tumors within the past 5 years. Current or prior use of immunosuppressants or systemic steroids (>10 mg/day prednisone equivalent) within 2 weeks prior to first dose.

Active autoimmune disease or history of autoimmune disease requiring systemic treatment.

Known immunodeficiency history, including HIV infection, organ transplant, or bone marrow transplant.

Uncontrolled concurrent diseases (e.g., uncontrolled hypertension, unstable angina, recent myocardial infarction, or severe infections).

Active tuberculosis (TB) or history of TB without standardized treatment. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Complete inability to take oral enteral nutrition due to esophageal stenosis. History or current presence of interstitial pneumonia or interstitial lung disease.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage.

Significant gastrointestinal disorders with severe diarrhea (CTCAE > Grade 2). Pregnant or lactating women. Participation in other clinical trials within 30 days prior to enrollment.

The individual participant data (IPD) that underlie the results reported in the primary publication, after de-identification (text, tables, figures, and appendices), will be shared with researchers to support the results.

Data will be available starting 6 months and ending 36 months following article publication.

Data will be available to researchers who provide a methodologically sound proposal to achieve the objectives in the approved proposal. Proposals should be directed to the corresponding author (Zhenyu Ding).