AI-Driven Digital Twin and Drug Simulation for Esophageal Cancer

Inclusion Criteria:

1. Treatment-naïve patients with clinical stage locally advanced (T1N1-3M0 or T2-3N0-3M0) thoracic esophageal squamous cell carcinoma, according to the 8th UICC-TNM staging system.
2. Cervical color Doppler ultrasound shows no suspicious metastatic lymph nodes, or patients with suspected lymph node metastasis on ultrasound who are eligible for three-field lymphadenectomy.
3. No prior antitumor therapy for esophageal cancer (including chemotherapy, radiotherapy, or immunotherapy).
4. Preoperative evaluation of organ function indicates no surgical contraindications.
5. Adequate bone marrow, liver, and renal function, confirmed by the following laboratory tests performed within 7 days prior to enrollment:

   * Hemoglobin ≥ 90 g/L;
   * White blood cell count ≥ 4.0 × 10\^9/L;
   * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L;
   * Platelet count ≥ 100 × 10\^9/L;
   * Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
   * ALT and AST ≤ 2.5 × ULN;
   * International normalized ratio (INR) of prothrombin time ≤ 1.5 × ULN, with activated partial thromboplastin time (APTT) within normal range;
   * Serum creatinine ≤ 1.5 × ULN.
6. No prior chemotherapy, radiotherapy, or hormone therapy for malignant tumors; no history of other malignancies, except for prostate cancer patients who received hormone therapy and have achieved disease-free survival (DFS) \> 5 years.
7. Expected to achieve R0 resection.
8. Eastern Cooperative Oncology Group (ECOG) performance status score 0 to 1.
9. Life expectancy ≥ 3 months.
10. Women of childbearing potential must agree to use effective contraceptive measures (e.g., intrauterine device, oral contraceptives, or condoms) during the study and for 6 months after study completion. Serum or urine pregnancy test must be negative within 7 days prior to enrollment, and patients must not be breastfeeding. Male patients must agree to use contraceptive measures during the study and for 6 months after study completion.
11. Patients must voluntarily participate in the study, provide written informed consent, demonstrate good compliance, and agree to follow-up.

Exclusion Criteria:

1. Patients not meeting the inclusion criteria.
2. Presence of multiple primary malignancies (synchronous or metachronous).
3. Active infections requiring systemic treatment.
4. Requirement for continuous systemic corticosteroid therapy (\>10 mg/day prednisone or equivalent) for comorbid conditions.
5. Unstable angina within 3 months or myocardial infarction within 6 months prior to enrollment.
6. Psychiatric disorders that may affect study compliance.
7. Known or concurrent hemorrhagic disorders.
8. Female patients who are pregnant or breastfeeding.
9. Patients with pre-existing or concurrent pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or other severe pulmonary impairment.
10. Autoimmune diseases, immunodeficiency states, or history of organ transplantation.
11. Known hypersensitivity to the study drugs (toripalimab, paclitaxel, cisplatin) or their excipients.
12. Abnormal coagulation function (PT \> 16s, APTT \> 53s, TT \> 21s, Fib \< 1.5 g/L), bleeding tendency, or patients receiving thrombolytic or anticoagulant therapy.
13. Bronchial asthma requiring intermittent use of bronchodilators or medical intervention.
14. Active hepatitis B (HBV) or hepatitis C (HCV) infection. (Patients who are HBsAg positive or HBcAb positive may be eligible if HBV DNA is below the lower limit of detection/quantification; patients who are HCV antibody positive may be eligible if HCV RNA is below the lower limit of detection/quantification.)
15. Human immunodeficiency virus (HIV) positivity.
16. Any other condition that, in the investigator's judgment, may compromise patient safety, interfere with study compliance, or preclude successful completion of the study.