This is a Phase II, open-label, single-arm, multicenter study evaluating the safety and efficacy of combining Tislelizumab with induction chemoradiotherapy (CRT), followed by conversion surgery, in patients with locally advanced, unresectable esophageal squamous cell carcinoma (ESCC).

Patients will receive induction CRT with weekly paclitaxel and cisplatin along with Tislelizumab, followed by two cycles of consolidation Tislelizumab-chemotherapy. If the tumor becomes resectable, patients will undergo surgery.

The primary goal is to assess the 2-year overall survival (OS) rate. Secondary outcomes include pathological complete response (pCR), conversion rate, R0 resection rate, disease-free survival (DFS), recurrence-free survival (RFS), and treatment-related adverse events.

Inclusion Criteria:

1. Patients had histologically confirmed, squamous-cell carcinoma of the esophagus

2. Clinical T4 cancer, at least one unresectable metastatic regional lymph node due to invasion into an adjacent organ, or computed tomographic (CT) evidence of M1Lym, such as fixed supraclavicular nodes. Regional lymph nodes are defined on the basis of criteria specified by the eighth edition of the Union for International Cancer Control TNM staging system (Sobin and Wittekind, 2016).

3. An age of at least 20 years

4. An Eastern Cooperative Oncology Group performance-status score 0 or 1

5. Adequate major organ functions

   • WBC ≥3,500/mm3

   • Hemoglobin ≥ 9.0 g/dL

   • Platelet ≥ 80,000/mm3

   • Total bilirubin ≤ 2-fold the upper limit of normal (ULN)

   • ALT and AST ≤ 5-fold the ULN AND ≤200 U/L

   • PT, aPTT and INR ≤1.5-fold the ULN

   • Albumin ≥2.5 g/dL

   • Creatinine clearance ≥50 ml/min (based upon 24 hours urine collection or calculated by Cockroft-Gault formula)

     • Male: ((140 - age) × weight [kg])/(72 × serum creatinine [mg/dL])
     • Female: 0.85 x estimate for male

6. Women of childbearing potential (including women with chemical menopause or no menstruation for other medical reasons) must agree to use contraception from the time of informed consent until 5 months or more after the last dose of investigational products. (Women of childbearing potential are defined as all women after the onset of menstruation who are not postmenopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy). Postmenopause is defined as amenorrhea for ≥12 consecutive months without specific reasons.)

7. Men must agree to use contraception from the start of study treatment until 3 months or more after the last dose of the investigational product.

8. Patients must be willing to undergo definitive resection with lymph node dissection

9. Participants must have signed written informed consent form in accordance with regulatory and institutional guidelines.

Exclusion Criteria:

1. Patient has received systemic therapy for advanced ESCC.

2. Patients had distant metastasis, including liver, lung, bone and brain metastases.

3. Patients had esophageal perforation or esophageal fistula

4. Patients had tumor bleeding

5. Patients had active infection(e.g. tuberculosis).

6. History or known human immunodeficiency virus.

7. Subjects with active, known, or suspected autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.

8. Systemic immunosuppression therapy or chronic systemic steroid therapy (more than 10mg daily of prednisolone)

9. Known hepatitis B (HBsAg reactive) or C virus infection (positive anti HCV)

   • Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable HBsAg or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for > 2 weeks before randomization/enrollment.
   • Patients with a positive HCV antibody test followed by a negative HCV RNA test at screening are eligible.

10. Previous therapy targeting T-cell costimulating or immune-checkpoint pathways

11. Prior or concurrent malignancies within the last 3 years, with the exception of carcinoma in situ of the cervix, or basal type skin cancer

12. Any major surgery within 4 weeks before study enrollment.

13. Pregnant women or nursing mothers, or positive pregnancy tests

14. Patients had allogeneic stem cell transplantation or organ transplantation.

15. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including NYHA Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.

16. Patients with interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including pulmonary fibrosis, or acute lung diseases

17. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.

18. Other patients judged by the investigators be inappropriate as subjects of this study