This is a single-arm, exploratory clinical study.

This study is a single-arm, single-center, prospective clinical trial. A total of 33 subjects are planned to be enrolled. The study consists of a screening period, a treatment period, and a post-treatment follow-up period. After providing signed informed consent and meeting eligibility criteria, subjects will receive neoadjuvant therapy with epacadostat, tovorafenib, lenvatinib, cisplatin/carboplatin, and nab-paclitaxel. Treatment will be administered in 3-week cycles, with a total of 3 preoperative cycles (lenvatinib will be discontinued in the third cycle).

Inclusion Criteria:

• Gender: no restriction; Age: 18-75 years.

• Histologically or cytologically confirmed diagnosis of esophageal squamous cell carcinoma.

• Clinical stage II-IVa (T2-4aN+M0) according to the AJCC 8th edition, and assessed as resectable by a multidisciplinary team (MDT).

• Complete imaging work-up shows no evidence of distant metastasis:

  1. Neck ultrasound and contrast-enhanced chest/abdominal CT.
  2. Ultrasound-guided lymph node biopsy or PET/CT if clinical suspicion or neck ultrasound suggests cervical lymph node metastasis.
  3. Abdominal non-contrast and contrast-enhanced MRI or PET/CT to confirm diagnosis if CT suggests liver metastasis.
  4. Bone scan if necessary in case of systemic bone pain symptoms.
  5. Endoscopic ultrasound for accurate staging.

• No prior antitumor therapy received (including radiotherapy, chemotherapy, targeted therapy, immunotherapy, or traditional Chinese medicine).

• ECOG Performance Status score: 0-1.

• Adequate organ function, meeting the following laboratory criteria (no blood transfusion, granulocyte colony-stimulating factor [G-CSF], or corrective medication within 14 days prior to treatment):

  1）Hemoglobin (Hb) ≥90 g/L. 2）Absolute neutrophil count (ANC) ≥1.5×10⁹/L. 3）Platelet count (PLT) ≥100×10⁹/L. 4）Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN). 5）Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN. 6）Serum creatinine clearance (CrCl) ≥50 mL/min (calculated by Cockcroft-Gault formula). 7）Coagulation: International normalized ratio (INR) ≤1.5 × ULN, activated partial thromboplastin time (APTT) ≤1.5 × ULN. 8）Proteinuria < 2+ (if ≥ 2+, a 24-hour urine protein quantification must be performed; patients are eligible if the result is ≤1 g). 9）Left ventricular ejection fraction (LVEF) ≥50%.

• No surgical contraindications.

• The subject agrees to use effective contraception from the signing of the informed consent form until 180 days after the last dose. Female subjects of childbearing potential must not be pregnant or breastfeeding.

• Subjects must voluntarily participate in this study, sign the informed consent form, demonstrate good compliance, and cooperate with follow-up.

Exclusion Criteria:

• Known history of hypersensitivity to macromolecular protein preparations. Contraindications or allergies to any component of epaplimut-pembrolizumab.
• Other anti-tumor therapies (chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, chemoembolization, anti-tumor traditional Chinese herbal medicine).
• Radiographic diagnosis indicating distant metastasis of the tumor.
• History of allogeneic tissue/solid organ transplantation.
• Within 2 weeks prior to the first dose, presence of a condition requiring systemic corticosteroid (>10 mg daily prednisone or equivalent) or other immunosuppressive medication (e.g., cyclophosphamide, azathioprine, methotrexate, thalidomide, TNF-α inhibitors, etc.). Topical, nasal spray, and inhaled corticosteroids are permitted. Prophylactic use of systemic corticosteroids for contrast agent allergy is allowed.
• Active or potentially recurrent autoimmune diseases, with the following exceptions: vitiligo, alopecia, psoriasis, or eczema not requiring systemic therapy; hypothyroidism due to autoimmune thyroiditis requiring only stable-dose hormone replacement therapy; type I diabetes requiring only stable-dose insulin replacement therapy.
• Other active malignancies within the past 5 years, except for cured localized cancers (e.g., basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast) and breast cancer without recurrence for more than 3 years after radical surgery.
• History of interstitial lung disease and/or pneumonitis or pulmonary hypertension.
• Poorly controlled ascites, pericardial effusion, or pleural effusion requiring repeated drainage.
• Poorly controlled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg) and diabetes despite standard treatment, or uncontrolled or symptomatic arrhythmia.
• Thromboembolic events within 6 months prior to the start of study treatment, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction) or pulmonary embolism.
• Myocardial infarction within the past 12 months, severe/unstable angina, or symptomatic congestive heart failure (NYHA class III or IV).
• Participation in other clinical trials within 60 days prior to or during the treatment period.
• Known active infection with HIV, HBV, or HCV.
• Major surgery (excluding needle biopsy) within 4 weeks prior to the first dose without full recovery.
• Any other condition deemed by the investigator as inappropriate for inclusion in this study.