Effective systemic therapy such as nivolumab as an adjuvant therapy has been demonstrated to improve the outcomes of patients receiving neoadjuvant chemoradiotherapy (CRT) for locoregional esophageal cancer. A more effective systemic therapy with anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors (ICIs) plus cisplatin-based doublet chemotherapy, which has shown with high tumor response rate and improved survivals in patients with late-stage ESCC, may provide crucial benefit to patients with locally advanced disease by improving the systemic control, downstaging the locoregional tumor burden and reducing recurrence and metastasis.

Collectively, the investigators hypothesize that total neoadjuvant therapy (TNT) approach-consisting of induction immunochemotherapy followed by CRT-is a promising strategy to enhance the outcomes for participants with locally advanced esophageal squamous cell carcinoma.

Inclusion Criteria:

1. Pathologically proven squamous cell carcinoma of the intrathoracic esophagus.

2. Locally advanced disease, which is defined by the TNM system of the American Joint Committee on Cancer (AJCC) Cancer Staging System (8th edition), fulfilling one of the following criteria as determined by staging procedures (including but not limited to endoscopic ultrasound, computed tomography, bronchoscopy or positron emission tomography):

   1. cT3/4a, N0, M0;
   2. cT1-4a, N1-3, M0.

3. Tumor length longitudinal ≤ 10cm and radial ≤ 5cm.

4. The tumor must not extend more than 2cm into the stomach.

5. No invasion of the tracheobronchial tree or presence of tracheoesophageal fistula.

6. Age ≥ 18 and ≤ 75 years old.

7. Performance status ECOG 0~1.

8. Adequate bone marrow reserves, defined as:

   1. white blood cells (WBC) ≥ 3,000/µl or neutrophil count (ANC) ≥ 1,500/µl;
   2. platelets ≥ 100,000/µl.

9. Adequate liver function reserves, defined as:

   1. hepatic transaminases ≤ 2.5 x upper limit of normal (ULN);
   2. serum total bilirubin ≤ 2.0 x upper limit of normal (ULN).

10. Adequate renal function: Creatinine ≤1.5 x upper normal limit or estimated creatinine clearance ≥ 50 ml/min (estimated by Cockcroft-Gault formulation)

11. Written informed consent.

12. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be mandatory.

13. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

14. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section - Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Adenocarcinoma

2. Previous thoracic irradiation

3. Previous systemic chemotherapy

4. Has received prior therapy with an anti-PD-1 or anti-PD-L1

5. Synchronous diagnosis of squamous cell carcinoma in the aerodigestive tract, other than esophageal cancer.

6. Prior malignancy, except for the following:

   1. adequately treated basal cell or squamous cell skin cancer;
   2. in-situ cervical cancer;
   3. a "cured" malignancy more than 5 years prior to enrollment.

7. Significant co-morbid disease, which prohibits the conduction of immunochemotherapy, concurrent CRT, or radical surgery, such as active systemic infection, symptomatic cardiac or pulmonary disease, or psychiatric disorders.

8. Documented myocardial infarction within the 6 months preceding registration (pretreatment ECG evidence of infarct only will not exclude patients). Patients with a history of significant ventricular arrhythmia requiring medication. Patients with a history of 2nd or 3rd degree heart block.

9. Pre-existing motor or sensory neurotoxicity greater than grade 1.

10. Patients with prior allergic reactions to drug containing Cremophor, such as teniposide or cyclosporine.

11. Weight loss > 15%.

12. Dementia or altered mental status that would prohibit the understanding and completion of informed consent.

13. Estimated life expectancy less than 3 months.

14. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

15. Has a known history of active TB (Bacillus Tuberculosis)

16. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

17. Has known history of, or any evidence of active, non-infectious pneumonitis, interstitial lung disease or pulmonary fibrosis.

18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

20. Patients with untreated chronic HBV or chronic HBV carriers whose HBV DNA is ≥500 IU/mL, or patients with active HCV. Patients who are inactive carriers or with treated and stable hepatitis B (detectable B surface antigen and HBV DNA <500 IU/mL); patients with non-reactive HCV can be enrolled. Patients with chronic HBV infection need to be treated with anti-HBV agents while receiving immunochemotherapy and chemoradiotherapy according to the local and institutional guidelines.

21. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines are live attenuated vaccines, and are not allowed.

22. Has received organ transplantation.

23. Has declined esophagectomy.