Low-Dose Radiotherapy With Retlirafusp Alfa and Chemotherapy as Neoadjuvant Therapy for Resectable Locally Advanced Esophageal Squamous Cell Carcinoma

Inclusion Criteria:

1. Voluntary participation with written informed consent.
2. Age 18-75 years, male or female.
3. Histologically or cytologically confirmed thoracic esophageal squamous cell carcinoma (ESCC).
4. Clinical stage T1-4aN1-3M0 or T3-4aN0M0 (AJCC 9th edition): T stage determined by CT combined with MRI or endoscopic ultrasound; nodal involvement confirmed by biopsy, EBUS/EUS, or mediastinoscopy, or imaging showing lymph node short-axis diameter ≥2.0 cm; distant metastasis (M1) excluded by FDG-PET/CT or chest/abdominal/brain CT/MRI; no suspicious metastatic lymph nodes on cervical ultrasound.
5. Potentially resectable thoracic esophageal lesion with anticipated R0 resection.
6. No prior systemic therapy for esophageal tumor (chemotherapy, targeted therapy, immunotherapy, radiotherapy, etc.).
7. ECOG performance status 0-1.
8. At least one measurable lesion per Japanese Classification of Esophageal Cancer, 12th edition.
9. Agreement to provide archived tumor tissue or undergo biopsy for biomarker analysis.
10. Adequate organ function (within 14 days prior to first dose, without blood products or growth factors):
11. Hematology: WBC ≥4×10⁹/L, ANC ≥2×10⁹/L, hemoglobin ≥90 g/L, platelets ≥90×10⁹/L.Hepatic: total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert's syndrome), AST and ALT ≤2.5×ULN (≤5×ULN for liver metastases), alkaline phosphatase ≤3×ULN (≤5×ULN for liver/bone metastases), albumin ≥30 g/L. Renal: serum creatinine ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault formula). Coagulation: INR ≤1.5 (without anticoagulation).
12. Body weight >35 kg, with no >10% weight loss in the past 3 months.
13. Life expectancy >12 months.
14. Women of childbearing potential and men must use effective contraception during the study and for 3 months after the last dose; non-lactating; negative serum/urine HCG within 7 days before first dose for women of childbearing potential.

Exclusion Criteria:

1.History of hypersensitivity to any component of Retlirafusp alfa, paclitaxel, carboplatin, or other platinum agents.

2,Cervical esophageal cancer, esophageal adenocarcinoma, or other pathological types.

3.Clinical stage I/IIA, T4b unresectable, or distant metastasis (M1) confirmed by imaging.

4.History of other malignancies within 5 years, except cured basal cell carcinoma of the skin, cervical carcinoma in situ, etc.

5.Prior or current receipt of any of the following:

1. Any radiotherapy, chemotherapy, or other anti-tumor therapy for malignancy.
2. Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) within 2 weeks prior to first study drug administration. Inhaled or topical steroids and adrenal hormone replacement at doses >10 mg/day prednisone or equivalent are permitted in the absence of active autoimmune disease.
3. Receipt of live-attenuated vaccine within 4 weeks prior to first study drug administration.
4. Major surgery or severe trauma within 4 weeks prior to first study drug administration.

6.Active or history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (may be considered after hormone replacement therapy). Patients with psoriasis or childhood asthma/allergy that has fully resolved and requires no intervention in adulthood may be considered; however, those requiring bronchodilators for medical intervention are excluded.

7.Immunodeficiency, including HIV positivity, other acquired or congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation.

8.Poorly controlled cardiac conditions, including but not limited to: (1) NYHA class ≥II heart failure, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias uncontrolled despite intervention.

9.Severe infection (CTCAE grade ≥2) within 4 weeks prior to first study drug administration, such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications; active pulmonary inflammation on baseline chest imaging; signs/symptoms of infection or need for oral/IV antibiotics within 14 days prior to first dose (except prophylactic antibiotics).

10.Active pulmonary tuberculosis by history or CT, history of active tuberculosis within 1 year prior to enrollment, or history of active tuberculosis >1 year ago without adequate treatment.

11.Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL), or hepatitis C (HCV antibody positive with HCV RNA above the lower limit of detection).

12.Diagnosis of other malignancy within 5 years prior to first study drug administration, except those with low risk of metastasis or death (5-year survival >90%), such as adequately treated basal cell or squamous cell skin cancer, or cervical carcinoma in situ.

13.Pregnant or lactating women. 14.Other conditions deemed by the investigator to potentially necessitate premature study termination, such as other serious diseases (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, or family/social factors that may affect patient safety or compliance.