Inclusion Criteria:
* Able to understand and voluntarily sign a written informed consent form, which must be signed before initiating any study-specific procedures.
* Male or female participants aged between 18 and 70 years at the time of informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Histologically or cytologically confirmed diagnosis of locally advanced esophageal squamous cell carcinoma (ESCC); or patients who refuse surgery; staged as T1-4bN1-3M0 (according to AJCC 8th edition).
* Medically inoperable or refusal of surgery.
* No prior anti-tumor treatment.
* Expected survival of at least 6 months.
* At least one measurable lesion as defined by RECIST v1.1.
* Participants must provide either archived (within the last 2 years) or freshly obtained tumor tissue samples, with at least three unstained FFPE pathology slides.
* Adequate organ function defined as follows:
a. Hematology (no blood transfusions or growth factor support within 7 days before starting study treatment): i. Absolute Neutrophil Count (ANC) ≥1.5×10\^9/L (1500/mm³); ii. Platelet count ≥100×10\^9/L (100000/mm³); iii. Hemoglobin ≥90 g/L. b. Renal: i. Calculated creatinine clearance (CrCl) ≥50 mL/min using the Cockcroft-Gault formula: CrCl (mL/min) = {(140-age) × weight (kg) × F} / (SCr (mg/dL) × 72), where F=1 for males and 0.85 for females; SCr=serum creatinine.
ii. Urinary protein \<2+ or 24-hour urinary protein quantification \<1.0 g. c. Liver: i. Total bilirubin (TBiL) ≤1.5×ULN; ii. AST and ALT ≤2.5×ULN (≤5×ULN for participants with liver metastases); iii. Serum albumin (ALB) ≥28 g/L. d. Coagulation: International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN, unless the participant is receiving anticoagulant therapy and INR and APTT are within the expected range of their therapeutic use.
e. Cardiac: Left Ventricular Ejection Fraction (LVEF) ≥50%.
* Female participants of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to the first dose of study medication. If urine test is not conclusive, a serum test will be administered. If sexually active with a non-sterilized male partner, the participant must agree to use effective contraception during the study and for 120 days after the last dose of study medication. Discussion with the researcher is required regarding cessation of contraception after this point.
* Male participants with female partners of childbearing potential must agree to use effective contraception from screening to 120 days after the last dose of study medication. Discussion with the researcher is required regarding cessation of contraception after this point.
* Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria:
* Previous anti-tumor treatment (including chemotherapy, radiation therapy, surgery, or immunotherapy).
* Initial diagnosis with metastases to vital organs such as the liver, bones, lungs, brain, adrenal glands, etc. (stage IVb esophageal cancer).
* History of thoracic radiotherapy.
* Presence of an esophageal mediastinal fistula and/or esophageal tracheal fistula before treatment.
* Known or suspected allergy to any component of S1, serplulimab, or cisplatin.
* Pregnant or breastfeeding women.
* Inability to provide informed consent due to psychological, familial, or social reasons.
* History of any malignancy other than esophageal cancer within the past 5 years, except for adequately treated non-melanoma skin cancer, in-situ cervical cancer, or cured early-stage prostate cancer.
* Unable to tolerate chemoradiation due to severe cardiac, pulmonary, hepatic, renal dysfunctions, hematological diseases, or cachexia.
* Active autoimmune diseases, history of autoimmune diseases (including but not limited to colitis, hepatitis, hyperthyroidism, or syndromes), history of immunodeficiency (including positive HIV test), or other acquired or congenital immunodeficiency diseases, history of organ transplant or allogeneic bone marrow transplant.
* Active hepatitis B (HBV DNA ≥ 2000IU/mL or 10×10\^4 copies/mL), positive hepatitis C antibody with elevated HCV RNA levels above the lower limit of detection.
History of immunodeficiency; positive HIV antibody; current long-term use of systemic corticosteroids or other immunosuppressants.
* Serious infection within 4 weeks before the first administration of study medication, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective treatment within 2 weeks before the first dose (excluding antiviral treatment for hepatitis B or C).
Known active tuberculosis (TB), suspected active TB requiring clinical exclusion; known active syphilis infection.
* Vaccination with live or attenuated live vaccines within 30 days before the first dose of study medication or planning to receive such vaccines during the study period; inactivated vaccines are permitted.
* History of interstitial lung disease or non-infectious pneumonia.
* History of myocarditis, cardiomyopathy, malignant arrhythmias, unstable angina, myocardial infarction within the past 12 months, congestive heart failure as determined by NYHA Class II or higher, or vascular diseases such as aortic aneurysm at risk of rupture, or other cardiac damage that could compromise the safety evaluation of the study medication (such as poorly controlled arrhythmia or myocardial ischemia).
* Known history of mental illness, drug abuse, alcoholism, or drug addiction.
* Non-malignant systemic diseases or symptoms secondary to tumors that could pose a higher medical risk or confound the assessment of survival, such as leukemic reaction (white cell count \>20×10\^9/L) or cachexia manifestations (known weight loss exceeding 10% in the 3 months prior to screening).
* Any condition that, in the opinion of the investigator, might pose a risk to the participant, interfere with the evaluation of the study medication, or confound the interpretation of study results.
