Esophageal cancer is a malignant tumor with high incidence rate and mortality in China. According to the data of the World Health Organization, 324000 new cases and 301000 deaths of esophageal cancer will occur in China in 2020, accounting for 53.70% and 55.35% of the global incidence and death of esophageal cancer respectively.

Surgery is the main method for locally advanced resectable esophageal cancer, combined with chemoradiotherapy(CRT), in order to achieve curative resection. However, after neoadjuvant chemoradiotherapy and surgery, 36-50% of patients still experience recurrence or metastasis, and the prognosis for early recurrence is worse. Adjuvant chemotherapy plays a particularly beneficial role in terms of disease-free survival(DFS) in patients who did not receive neoadjuvant therapy and patients with pathologic lymph-node-positive disease. however, less than 50% of eligible patients receive their scheduled adjuvant chemotherapy due to delays, treatment compliance, and postoperative complications. Among patients with resected esophageal cancer who had received neoadjuvant CRT, DFS was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo.

Total neoadjuvant therapy (TNT), attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery, which may become a new treatment direction for patients with locally advanced resectable esophageal cancer. Ongoing progress in all treatment modalities involved in TNT holds the promise to enhance further the outcomes of patients with esophageal cancer. Immunotherapy, as a breakthrough therapy in the systemic treatment of advanced esophageal cancer, has become an indispensable component of the exploration of TNT model. Currently, several prospective exploratory studies suggest that immunotherapy combined with TNT can improve the pCR rate of esophageal cancer patients, achieving good short-term efficacy and tolerable safety.

However, further exploration is needed for the combination of immunotherapy and TNT. This study first explores the efficacy and safety of two types of total neoadjuvant therapy in phase II: the combination of adebrelimab and chemotherapy followed by chemoradiotherapy, or the combination of adebrelimab and chemotherapy after chemoradiotherapy. A more promising treatment plan will be selected for a phase III randomized controlled trial and confirm the superiority of adebrelimab combined with TNT over neoadjuvant CRT in terms of pathological complete response overall survival in patients with locally advanced resectable esophageal cancer.

Inclusion Criteria:

1. Sign a informed consent form and voluntarily join this study;

2. Esophageal squamous cell carcinoma diagnosed by histopathology or cytology;

3. Diagnosed as thoracic esophageal cancer by CT/MRI/EUS and clinically staged as T1b-3N1-2M0 or T3N0M0 (according to AJCC 8th edition);

4. Expected to achieve R0 resection;

5. Age ≥ 18 years old, regardless of gender;

6. ECOG PS 0-1;

7. Have not received any anti-tumor treatment for esophageal cancer in the past;

8. Plan to undergo surgical treatment after completion of neoadjuvant therapy;

9. No surgical contraindications;

10. The main organ functions are normal, including:

    1. Blood routine examination:

       neutrocyte count ≥ 1.5 × 109/L Platelet count ≥ 100 × 109/L Hemoglobin ≥ 90 g/L

    2. Blood biochemistry test:

       Total bilirubin ≤ 1.5 × ULN ALT ≤ 2.5×ULN，AST ≤ 2.5×ULN， Serum creatinine ≤ 1.5 × ULN, or creatinine clearance rate ≥ 50 mL/min (Cocheroft Gault formula, see Appendix 2)

    3. Coagulation function:

    INR ≤ 1.5 × ULN APTT ≤ 1.5 × ULN

11. Women who have the ability to conceive or men whose spouses have the ability to conceive should use effective contraceptive measures during the study period;

12. The subjects showed good compliance and cooperated with follow-up visits;

Exclusion Criteria:

1. Tumors or lymph nodes significantly invade adjacent organs of esophageal lesions;

2. Patients with supraclavicular lymph node metastasis;

3. Individuals at risk of perforation, fistula, etc;

4. There are uncontrollable pleural effusion, pericardial effusion, or ascites that require repeated drainage;

5. Poor nutritional status, BMI < 18.5 Kg/m2；

6. Have a history of allergies to monoclonal antibodies, any components of Adebrelimab, paclitaxel, cisplatin, or other platinum based drugs in the past;

7. Have received or are currently receiving any of the following treatments:

   1. Any radiotherapy, chemotherapy, or other anti-tumor drugs targeting tumors;
   2. Within 2 weeks prior to the first use of the investigational drug, immunosuppressive or systemic hormone therapy was being used to achieve immunosuppressive effects;
   3. Received attenuated live vaccine within 4 weeks prior to the first use of the investigational drug;
   4. Having undergone major surgery or suffered severe trauma within 4 weeks prior to the first use of the investigational drug;

8. Suffering from any active autoimmune disease or history of autoimmune disease;

9. History of immunodeficiency, including HIV testing positive, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation;

10. There are clinical symptoms or diseases of the heart that have not been well controlled;

11. Severe infection (CTCAE>grade 2) occurred within 4 weeks prior to the first use of the investigational drug;

12. Discovery of active pulmonary tuberculosis infection through medical history or CT examination;

13. Active hepatitis B and hepatitis C exist;

14. Diagnosed with other malignant tumors within 5 years prior to the first use of the investigational drug;

15. Pregnant or lactating women;

16. According to the researchers' assessment, there are other factors that may lead to the forced termination of the study midway.

After the conclusion of the study, Individual Participant Data (IPD) will be shared through the publication of articles.

After the study concludes, please contact the principal investigator for specifics.

Please contact the principal investigator.