This is a prospective, single-arm, exploratory clinical study designed to evaluate the efficacy and safety of retlirafusp alfa combined with chemotherapy (nab-paclitaxel and cisplatin) as a neoadjuvant therapy for patients with resectable locally advanced thoracic esophageal squamous cell carcinoma (ESCC).

The primary objective of this study is to assess the pathologic complete response (pCR) rate in the target population. A total of 33 patients with histologically or cytologically confirmed resectable locally advanced thoracic ESCC are planned to be enrolled.

The study comprises three sequential phases: a Screening Period, a Treatment Period, and a Follow-up Period.

Screening Period: Conducted within a maximum of 21 days from the signing of the Informed Consent Form (ICF) up to the first administration of the study drug.

Treatment Period: Includes both the neoadjuvant therapy phase and the subsequent surgical resection.

Follow-up Period: Consists of safety follow-up, tumor progression/recurrence follow-up, and overall survival follow-up.

Neoadjuvant Regimen and Administration Schedule:

Patients will receive 3 cycles of neoadjuvant therapy consisting of retlirafusp alfa combined with nab-paclitaxel and cisplatin. Surgical resection is scheduled to be performed 4 to 6 weeks following the completion of the neoadjuvant therapy.

A dosing window of ±3 days is permissible during the study treatment period. Prior to each administration (within 3 days before dosing), subjects must undergo standard safety evaluations, including physical examinations (as needed), laboratory tests, and Eastern Cooperative Oncology Group (ECOG) performance status assessments, to confirm treatment tolerance. Laboratory tests completed during the screening period within the protocol-specified timeframe do not need to be repeated prior to the first dose. Safety assessments will be continuously monitored throughout the study duration to ensure subject safety.

Inclusion Criteria:

1. Voluntarily signed and dated written informed consent to participate in this study.
2. Histologically or cytologically confirmed esophageal squamous cell carcinoma (ESCC).
3. Clinically staged as thoracic ESCC evaluated by CT, MRI, or endoscopic ultrasonography (EUS), with a clinical stage of T1b-4aN+M0 or T2-4N0M0 according to the American Joint Committee on Cancer (AJCC) 8th edition. For T2N0 patients, at least one high-risk factor must be present: lymphovascular invasion (LVI), tumor size >= 3 cm, or poor differentiation.
4. Anticipated to achieve an R0 resection.
5. Age between 18 and 75 years (inclusive) at the time of signing the informed consent, of either sex.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. No prior anti-tumor therapy for esophageal cancer, including radiotherapy, chemotherapy, or surgery.
8. Planned to undergo definitive surgical resection following the completion of neoadjuvant therapy.
9. No contraindications to surgical resection.
10. Adequate major organ functions, meeting the following laboratory criteria: 10a) Hematology (no blood components, cell growth factors, leukogenic agents, platelet-stimulating agents, or anemia-correcting therapies allowed within 14 days prior to the first dose of study drug): Absolute neutrophil count (ANC) >= 1.5 x 10^9/L; Platelet count >= 100 x 10^9/L; Hemoglobin >= 90 g/L. 10b) Blood Biochemistry: Total bilirubin (TBIL) <= 1.5 x Upper Limit of Normal (ULN); Alanine aminotransferase (ALT) <= 2.5 x ULN; Aspartate aminotransferase (AST) <= 2.5 x ULN; Serum creatinine <= 1.5 x ULN, or creatinine clearance (CrCl) >= 50 mL/min. 10c) Coagulation Function: International Normalized Ratio (INR) <= 1.5 x ULN; Activated Partial Thromboplastin Time (APTT) <= 1.5 x ULN.
11. Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to the first dose of study drug and agree to use highly effective methods of contraception (e.g., intrauterine device [IUD], contraceptives, or condoms) during the trial and for at least 3 months after the last dose. Male subjects whose partners are females of childbearing potential must be surgically sterile or agree to use highly effective contraception during the trial and for at least 3 months after the last dose.
12. Good compliance and willingness to cooperate with the scheduled follow-up visits.

Exclusion Criteria:

1. Tumors with clear invasion into adjacent organs of the esophageal lesion (e.g., aorta or trachea).
2. Presence of supraclavicular lymph node metastasis.
3. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage.
4. Poor nutritional status with Body Mass Index (BMI) < 18.5 kg/m2; however, patients whose nutritional status is corrected after symptomatic nutritional support before enrollment may still be considered after evaluation by the principal investigator.
5. Known history of hypersensitivity to the study drugs.
6. Prior or current receipt of any of the following treatments: 6a) Any prior anti-tumor radiotherapy, chemotherapy, or other anti-tumor medications. 6b) Use of immunosuppressive medications or systemic corticosteroid therapy for immunosuppressive purposes (dose > 10 mg/day of prednisone or equivalent dose) within 2 weeks prior to the first dose of study drug. 6c) Receipt of live attenuated vaccines within 4 weeks prior to the first dose of study drug. 6d) Major surgery or severe trauma within 4 weeks prior to the first dose of study drug.
7. Active autoimmune disease or a history of autoimmune disease, including but not limited to: interstitial lung disease, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism (subjects stable on hormone replacement therapy can be considered for inclusion). Subjects with psoriasis or childhood asthma/allergies that have completely resolved without any adult intervention may be considered for inclusion; however, patients requiring medical intervention with bronchodilators are excluded.
8. History of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation or allogeneic bone marrow transplantation.
9. Uncontrolled clinical cardiac symptoms or diseases, including but not limited to: (1) New York Heart Association (NYHA) Class II or higher heart failure, (2) unstable angina, (3) myocardial infarction within the past 1 year, (4) clinically significant supraventricular or ventricular arrhythmias that are uncontrolled or poorly controlled despite clinical intervention.
10. Severe infection (CTCAE > Grade 2) within 4 weeks prior to the first dose of study drug, such as severe pneumonia, bacteremia, or infectious complications requiring hospitalization; baseline chest imaging indicating active pulmonary inflammation, signs or symptoms of infection within 14 days prior to the first dose of study drug, or requiring oral or intravenous antibiotic therapy (except for prophylactic antibiotic use).
11. Active tuberculosis infection detected by medical history or CT scan, or a history of active tuberculosis infection within 1 year prior to enrollment, or a history of active tuberculosis infection more than 1 year ago without formal standard treatment.
12. Screening imaging showing tumor encasement of major blood vessels or significant necrosis/cavitation, where the investigator judges that study participation would pose a high risk of hemorrhage.
13. Active hepatitis B (HBV DNA >= 2000 IU/mL or 10^4 copies/mL), or hepatitis C (HCV antibody positive and HCV RNA above the lower limit of detection of the assay).
14. Diagnosis of other malignant tumors within 5 years prior to the first dose of study drug, unless the malignancy carries a low risk of metastasis or death (5-year survival rate > 90%), such as adequately treated basal cell carcinoma, squamous cell skin cancer, or cervical carcinoma in situ.
15. Pregnant or lactating females.
16. Any other factors that, in the judgment of the investigator, may compel premature termination of study participation, such as other severe medical or psychiatric conditions requiring concomitant therapy, alcohol abuse, drug abuse, familial or social factors, or any other conditions that may compromise subject safety or compliance.