The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin as neoadjuvant therapy followed by surgery, and pembrolizumab as adjuvant therapy, compared with neoadjuvant chemoradiotherapy and surgery for locally advanced ESCC in multicenter.

Preoperative chemoradiotherapy with radical surgery is the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC) in the NCCN guidelines. But many patients refused or abandon radiotherapy because of the intolerable adverse effects. The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin as neoadjuvant therapy followed by surgery, and pembrolizumab as adjuvant therapy, compared with neoadjuvant chemoradiotherapy and surgery for locally advanced ESCC in multicenter. The primary study hypothesis is that Event Free Survival (EFS) is superior with pembrolizumab plus neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy in participants with ESCC.

Inclusion Criteria:

1. Histologically confirmed esophageal squamous cell carcinoma;
2. R0 resectable thoracic esophageal cancer, cT1-3N1-2M0, cT2-3N0M0 (AJCC V8 TNM classification);
3. No suspicious metastatic lymph nodes on the clavicle;
4. Have a performance status of 0 or 1 on the ECOG Performance Scale;
5. Age 18-75 years old, both men and women;
6. Be willing and able to provide written informed consent/assent for the trial;
7. Demonstrate adequate organ function ;
8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours before 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 required;
9. Be willing to provide tissue, blood, and urine samples. Tissue should be from a newly obtained core or excisional biopsy of a tumor lesion through repeated biopsies. Newly-obtained is defined as a specimen obtained up to 4 weeks (28 days) before initiation of treatment on Day 1.
10. Have not received systemic or local treatment for esophageal cancer in the past.

Exclusion Criteria:

1. Ineligibility or contraindication for esophagectomy;
2. Prior therapy (operation, radiotherapy, immunotherapy, or chemotherapy) for esophageal cancer
3. Active autoimmune disease or history of autoimmune disease;
4. Requiring systemic treatment with either corticosteroids or other immunosuppressive medications;
5. Subjects with a history of symptomatic interstitial lung disease;
6. History of allergy to study drug components;
7. Women must not be pregnant or breast-feeding;
8. Patient has received prior chemotherapy, radiotherapy, target therapy ，and immune therapy for this malignancy or any other past malignancy;
9. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.