Neoadjuvant Short-Course Radiotherapy Plus Tislelizumab and Chemotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma

Neoadjuvant Short-Course Radiotherapy Followed by Tislelizumab Plus Chemotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma This is a prospective, randomized, two-arm, parallel-group, multicenter, exploratory Phase II clinical trial. It aims to evaluate the efficacy and safety of neoadjuvant short-course radiotherapy followed by tislelizumab combined with chemotherapy in participants with locally advanced resectable esophageal squamous cell carcinoma (ESCC). Eligible participants will be randomized in a 1:1 ratio to receive either low-dose or high-dose short-course radiotherapy, followed by tislelizumab, nab-paclitaxel, and carboplatin for 3 cycles. Surgery will be performed 4-6 weeks after the last neoadjuvant treatment. Primary endpoint: Pathological Complete Response (pCR) rate. Secondary endpoints: Major Pathological Response (MPR) rate, Objective Response Rate (ORR), R0 resection rate, downstaging rate, 3-year Event-Free Survival (EFS), 3-year Overall Survival (OS), safety profile, and quality of life. Approximately 50 participants will be enrolled. Randomization will be stratified by tumor location, clinical T stage, and clinical N stage using a stratified block design via an EDC/IWRS system.

Inclusion Criteria: * Voluntarily provided written informed consent prior to any study-related procedures * Aged 18 to 75 years, male or female * Life expectancy of at least 3 months * Predicted to achieve R0 surgical resection * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Histologically confirmed, treatment-naive, resectable locally advanced thoracic esophageal squamous cell carcinoma (ESCC) meeting the staging criteria: T1 N1-3 M0 or T2-4a N0-3 M0 (T2 ≥3 cm or poorly differentiated). No suspected metastatic cervical lymph nodes (except for upper thoracic esophageal cancer regional lymph nodes) on neck ultrasound or contrast-enhanced CT, and no distant metastasis on imaging * Presence of measurable tumor lesions. * Adequate organ function defined by laboratory parameters: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count ≥100×10⁹/L; hemoglobin ≥90 g/L. Total bilirubin ≤1.5×ULN; AST and ALT ≤2.5×ULN. Serum creatinine ≤1.5×ULN or calculated creatinine clearance ≥60 mL/min. INR ≤1.5, PT and APTT ≤1.5×ULN * Men and women of childbearing potential must use effective contraception during treatment and for 6 months after the last dose of study treatment * Good compliance and ability to complete scheduled follow-up. Exclusion Criteria: * Prior treatment with PD-1/PD-L1 inhibitors or other immunomodulatory agents targeting T-cell receptors (e.g., CTLA-4, OX40) * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage * Active or suspected autoimmune disease, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, except type 1 diabetes controlled by replacement therapy, hypothyroidism, or skin disorders not requiring systemic therapy * History of grade ≥2 interstitial lung disease * Systemic corticosteroids (\>10 mg prednisone daily or equivalent) or other immunosuppressive agents within 14 days before first study treatment * Primary or acquired immunodeficiency, organ transplantation, allogeneic hematopoietic stem cell transplantation * Live vaccine within 4 weeks before first study treatment * Severe uncontrolled cardiovascular or cerebrovascular disease: Uncontrolled hypertension or pulmonary hypertension. Unstable angina, myocardial infarction, coronary artery bypass grafting, or stent implantation within 6 months. NYHA class ≥2 chronic heart failure. Left ventricular ejection fraction (LVEF) \