This is a prospective, open-label, randomized phase II clinical trial designed to compare the efficacy and toxicity of hypofractionated concurrent chemoradiotherapy versus conventional fractionated concurrent chemoradiotherapy following induction chemoimmunotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma.

This is a prospective, open-label, randomized phase II clinical trial designed to compare the efficacy and toxicity of hypofractionated concurrent chemoradiotherapy versus conventional fractionated concurrent chemoradiotherapy following induction chemoimmunotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma. In this study, patients will receive induction therapy with albumin-bound paclitaxel and cisplatin combined with toripalimab. After induction therapy, they will be randomly assigned to receive either definitive hypofractionated concurrent chemoradiotherapy or conventional fractionated concurrent chemoradiotherapy. Following the completion of treatment, patients will undergo regular follow-up to assess efficacy and safety.

Inclusion Criteria:

• Pathologically or cytologically confirmed diagnosis of esophageal squamous cell carcinoma;
• Evaluated as unresectable locally advanced esophageal squamous cell carcinoma by endoscopic ultrasound, imaging studies including esophagography, CT of the neck, chest, and upper abdomen, MRI of the neck and chest, whole-body bone scan, or PET/CT, with staging in the range of II-IVB (stage IVB limited to celiac lymph node or supraclavicular lymph node metastasis);
• Male or female aged 18 to 80 years;
• Eligible for oral drug therapy;
• No prior chemotherapy, radiotherapy, surgery, targeted therapy, or immunotherapy;
• Tumor sample requirement: Must provide adequate unstained, archived tumor tissue samples for analysis;
• Expected survival ≥12 weeks;
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1;
• Postmenopausal women, or women with a negative urine or serum pregnancy test within 14 days before the study drug administration;
• Women must not be breastfeeding;
• Organ and bone marrow function must meet the following criteria: Forced expiratory volume in 1 second (FEV1) ≥1000 mL; Absolute neutrophil count ≥1.5 × 10^9/L; Platelets ≥100 × 10^9/L; Hemoglobin ≥90 g/L; Estimated glomerular filtration rate (eGFR) ≥50 mL/min based on the Cockcroft-Gault formula (Cockcroft and Gault, 1976); Serum bilirubin ≤1.5 × the upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN;
• Signed and dated informed consent must be provided before participation in any study procedures.

Exclusion Criteria:

Exclusion Criteria for Induction Treatment:

• Participation in another clinical trial, unless it is an observational (non-interventional) study;
• Use of immunosuppressive drugs within 28 days prior to the first infusion of Toripalimab, excluding physiological doses of intranasal inhaled corticosteroids, prednisone ≤10 mg/day, or equivalent systemic corticosteroids;
• Prior use of any anti-PD-1 or anti-PD-L1 antibody;
• Major surgery within 4 weeks prior to entering the study (excluding vascular access procedures);
• A history of autoimmune disease within the past 2 years;
• Active or a history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis);
• History of primary immunodeficiency;
• History of organ transplantation requiring immunosuppressive treatment;
• Uncontrolled complications, including but not limited to persistent or active infections, symptomatic congestive heart failure, poorly controlled hypertension, unstable angina, arrhythmias, active peptic ulcer disease or gastritis, active bleeding disorders, including any known HBsAg-positive patients with HBV DNA >500 IU/ml, hepatitis C, or HIV, or any psychiatric or social conditions that would impair the ability to comply with study requirements or harm the patient's ability to provide written informed consent;
• Receipt of a live attenuated vaccine within 30 days prior to study initiation or within 30 days after receiving Toripalimab;
• History of another primary malignancy within 5 years prior to the initiation of Toripalimab treatment, excluding adequately treated skin basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the cervix;
• Pregnancy, breastfeeding women, or men and women of reproductive potential who are not using effective contraception.

Exclusion Criteria for Concurrent Chemoradiotherapy After Induction Treatment:

• Development of distant metastasis (excluding celiac lymph node or supraclavicular lymph node metastasis);
• Development of local regional progression, with the radiation oncologist assessing that the patient cannot receive definitive chemoradiotherapy due to normal tissue dose limitations;
• PS score of 2-4;
• Any of the following organ and bone marrow dysfunction criteria: FEV1 <1000 mL; absolute neutrophil count <1.5 × 10^9/L; platelets <100 × 10^9/L; hemoglobin <90 g/L; serum creatinine clearance <50 mL/min according to the Cockcroft-Gault formula (Cockcroft & Gault, 1976); serum bilirubin >1.5 times the upper limit of normal (ULN); ALT and AST >2.5 times ULN.