This is a prospective, multi-cohort, exploratory clinical study designed to evaluate the efficacy and safety of neoadjuvant adebrelimab combined with chemotherapy in patients with resectable locally advanced thoracic esophageal squamous cell carcinoma (ESCC), with a particular focus on the effect of the time-of-day of immunotherapy infusion.

Eligible patients with histologically or cytologically confirmed, resectable locally advanced thoracic ESCC will be randomly assigned in a 1:1:1 ratio to three cohorts according to predefined immunotherapy infusion time windows. Cohort A will receive adebrelimab plus chemotherapy with the first cycle initiated at or after 15:00 and subsequent cycles initiated before 15:00; Cohort B will receive all three cycles initiated before 15:00; and Cohort C will receive all three cycles initiated at or after 15:00. Neoadjuvant treatment consists of three cycles of adebrelimab in combination with nab-paclitaxel and cisplatin, followed by surgical resection 4-6 weeks after completion of neoadjuvant therapy.

The primary endpoint of the study is pathological complete response (pCR). Secondary endpoints include event-free survival (EFS), major pathological response (MPR) rate, R0 resection rate, overall survival (OS), and disease-free survival (DFS).

Tumor response will be assessed according to RECIST version 1.1, and pathological response will be evaluated using the College of American Pathologists (CAP) tumor regression grading system and AJCC 8th edition staging criteria. Safety will be continuously monitored throughout the study, and patients will undergo scheduled follow-up for disease progression or recurrence and survival after completion of study treatment.

Inclusion Criteria:

1. Patients who have signed a written informed consent form and voluntarily agree to participate in the study.

2. Histologically or cytologically confirmed esophageal squamous cell carcinoma.

3. Tumor located in the thoracic esophagus, assessed by CT, MRI, EUS, or other imaging modalities, with clinical stage T1b-4aN+M0 or T2-4N0M0 (T2N0 patients must have high-risk features: lymphovascular invasion [LVI], tumor ≥3 cm, or poor differentiation) according to AJCC 8th edition.

4. Tumors deemed potentially resectable with R0 margins.

5. Age between 18 and 75 years, male or female.

6. ECOG performance status of 0 or 1.

7. No prior anti-tumor treatment for esophageal cancer, including surgery, radiotherapy, or chemotherapy.

8. Planned to undergo surgery after completion of neoadjuvant therapy.

9. No contraindications to surgery.

10. Adequate organ function, including:

    1. Hematologic parameters(no blood products, growth factors, erythropoiesis-stimulating agents, or platelet-stimulating drugs within 14 days prior to first study drug administration): Absolute neutrophil count ≥1.5 × 10⁹/L;Platelet count ≥100 × 10⁹/L;Hemoglobin ≥90 g/L.
    2. Biochemical parameters:Total bilirubin ≤1.5 × ULN; ALT ≤2.5 × ULN, AST ≤2.5 × ULN;Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min.
    3. Coagulation parameters:International normalized ratio (INR) ≤1.5 × ULN; Activated partial thromboplastin time (APTT) ≤1.5 × ULN.

11. For women of childbearing potential, a negative serum pregnancy test within 72 hours prior to first study drug administration and agreement to use effective contraception during the study and for at least 3 months after the last dose (e.g., intrauterine device, oral contraceptives, or condoms). Male participants with partners of childbearing potential must be surgically sterilized or agree to use effective contraception during the study and for at least 3 months after the last dose.

12. Good compliance and willingness to adhere to study procedures and follow-up. ---

Exclusion Criteria:

1. Tumor with obvious invasion of adjacent critical structures, such as the aorta or trachea.

2. Presence of supraclavicular lymph node metastasis.

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

4. Poor nutritional status with body mass index (BMI) <18.5 kg/m²; patients whose nutritional status is corrected before randomization through supportive care may be considered eligible at the discretion of the principal investigator.

5. Known hypersensitivity to monoclonal antibodies, adebrelimab, nab-paclitaxel, cisplatin, or other platinum-based agents.

6. Prior or ongoing treatments as follows:

   1. Any prior anti-tumor therapy, including chemotherapy, radiotherapy, or other anti-cancer drugs;
   2. Use of systemic immunosuppressive therapy or corticosteroids for immunosuppression (>10 mg/day prednisone or equivalent) within 2 weeks prior to first study drug administration. Inhaled or local steroid use and corticosteroid replacement therapy >10 mg/day prednisone equivalent in patients without active autoimmune disease are permitted;
   3. Administration of live attenuated vaccines within 4 weeks prior to first study drug administration;
   4. Major surgery or severe trauma within 4 weeks prior to first study drug administration.

7. Active autoimmune disease or history of autoimmune disease, including but not limited to interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism (patients on stable hormone replacement therapy may be eligible). Patients with psoriasis or childhood asthma/allergy fully resolved in adulthood and not requiring intervention may be eligible, but those requiring ongoing medical management with bronchodilators are excluded.

8. History of immunodeficiency, including positive HIV test, other congenital or acquired immunodeficiency, or history of organ or allogeneic bone marrow transplantation.

9. Uncontrolled clinically significant cardiac conditions, including but not limited to:

   NYHA class II or higher heart failure;Unstable angina;Myocardial infarction within 1 year;Clinically significant supraventricular or ventricular arrhythmias inadequately controlled despite intervention.

10. Severe infection (CTCAE > grade 2) within 4 weeks prior to first study drug administration requiring hospitalization, including severe pneumonia, bacteremia, or infectious complications. Patients with active pulmonary inflammation on baseline imaging, infection symptoms within 14 days prior to first study drug administration, or requiring oral/IV antibiotics (excluding prophylactic antibiotics) are excluded.

11. Active pulmonary tuberculosis, history of active tuberculosis within 1 year prior to enrollment, or history of untreated active tuberculosis more than 1 year prior to enrollment.

12. Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL) or hepatitis C infection (positive HCV antibody with HCV RNA above the assay detection limit).

13. Diagnosis of other malignancies within the past 5 years, except for tumors with low risk of metastasis or mortality (5-year survival >90%), such as adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.

14. Pregnant or breastfeeding women.

15. Any other condition that, in the opinion of the investigator, could lead to premature discontinuation of study treatment or compromise participant safety or compliance, including serious comorbidities (including psychiatric disorders requiring concomitant therapy), alcohol or substance abuse, or social/familial factors.