The aim of this clinical trial is to evaluate the efficacy and safety of consolidation therapy with a neoantigen-loaded dendritic cell vaccine (NeoDC-Vac) following radical chemoradiotherapy or chemoradiation-immunotherapy in patients with locally advanced, unresectable ESCC. The primary endpoint of the study is the OS rate. Secondary endpoints include OS, PFS, adverse events, CR rate, and quality of life (QoL) of patients. Exploratory endpoints involve the assessment of biomarkers such as TMB, PD-L1, and ctDNA.

The key questions this study aims to answer are:

-Can the combination of (ICIs and NeoDC-Vac as maintenance therapy improve OS and QoL in patients with locally advanced, unresectable ESCC following radical treatment? Can this novel approach provide an effective treatment option for these patients?

Participant Procedures:

1. Endoscopic examination at West China Hospital. Baseline fresh tumor tissue collection for NGS in neoantigen vaccine group.

2. Screening assessments, informed consent, and random assignment to experimental or control group.

   Experimental Group**: Neoantigen-loaded vaccine + standard ICIs as maintenance therapy.

   Control Group**: Standard ICIs as maintenance. One cycle per month for one year.

3. Tumor tissue NGS, ctDNA analysis, TIME evaluation, T cell response profiling. All costs covered by research funding.

4. After completing the full treatment regimen, participants will be monitored with regular follow-up visits by healthcare professionals to assess ongoing health outcomes and safety.

The objective of this clinical trial is to evaluate the efficacy and safety of neoantigen-loaded dendritic cell (DC) vaccines as consolidation therapy following definitive chemoradiotherapy or radiotherapy with immunotherapy in patients with locally advanced unresectable esophageal squamous cell carcinoma (ESCC). The primary endpoint is the 2-year overall survival (OS) rate. Secondary endpoints include OS, progression-free survival (PFS), adverse events, complete response (CR) rate, and patient quality of life. Exploratory endpoints focus on biomarker analysis, including tumor mutational burden (TMB), PD-L1 expression, and circulating tumor DNA (ctDNA).

The key questions this study aims to answer are whether maintenance therapy with immune checkpoint inhibitors (ICIs) combined with neoantigen vaccines can improve overall survival and quality of life in patients with locally advanced, unresectable ESCC following definitive treatment, ultimately providing a new therapeutic strategy for these patients.

**Participants in the study will:**

1. **Diagnostic Endoscopy at West China Hospital:** Participants must undergo endoscopic examination at West China Hospital to confirm diagnosis. For patients in the neoantigen vaccine group, baseline fresh tissue samples will be obtained for next-generation sequencing (NGS) to screen for neoantigen peptides, which will be used to prepare individualized neoantigen vaccines.

2. **Enrollment and Consent:** Participants will complete relevant examinations to determine eligibility. Upon confirmation of eligibility, they will provide informed consent and undergo randomization.

   **Treatment Regimen:**

   • **Experimental Group:** Neoantigen tumor vaccine in combination with standard immune checkpoint inhibitors (ICIs) as maintenance therapy following definitive treatment.
   • **Control Group:** Standard ICIs alone as maintenance therapy.

   The treatment cycle will consist of monthly administrations for a total duration of one year.

3. **Assessments During Treatment:** Key assessments during treatment will include NGS sequencing of tumor tissue, ctDNA analysis from blood samples, evaluation of the tumor immune microenvironment (TIME), and T-cell response analysis. All of these assessments are essential for receiving the study treatment, and the associated costs will be covered by the research grant, ensuring that participants incur no additional financial burden.

Inclusion Criteria:

A. Age 18-80 years

B. Locally advanced unresectable ESCC patients after radical treatment (radical chemoradiotherapy or chemoradiation); including:

• Cervical esophageal segment, T4, supraclavicular lymph node metastasis, or inability/refusal to undergo surgery due to personal reasons (refer to hospital below); ② Failure of neoadjuvant or conversion therapy; ③ Postoperative local recurrence, unresectable (target lesion present). C. No evidence of tumor recurrence or metastasis 2-3 weeks after radical treatment D. Ability to provide fresh tumor tissue samples (baseline) E. Normal major organ function F. Performance status (PS) score ≤ 1 G. Patients of childbearing potential must use contraception H. Voluntary participation with signed informed consent

Exclusion Criteria:

A. History of fistula caused by primary tumor invasion B. High risk of gastrointestinal bleeding, esophageal fistula, or esophageal perforation C. Poor nutritional status D. Immune-related adverse events during prior radical treatment, such as Grade ≥3 pneumonitis, myocarditis, etc.

E. Signs and symptoms of interstitial diseases F. Presence of any severe and/or uncontrolled medical conditions G. Presence of concurrent malignancies H. Presence of other autoimmune diseases, or prolonged use of immunosuppressants or steroids I. Difficulty in patient communication or inability to comply with long-term follow-up J. Other conditions deemed unsuitable by the investigator