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Background Esophageal squamous cell carcinoma (ESCC) patients with a suboptimal pathological response (non-pCR/mPR) after neoadjuvant chemoimmunotherapy and radical surgery represent a high-risk population for recurrence. This investigator-initiated trial ( NCT05307835) evaluated the safety and efficacy of iNeo-Vac-P01, a personalized neoantigen peptide vaccine, as adjuvant therapy in this high-risk population. To our knowledge, this represents one of the first and largest clinical studies globally reporting outcomes of a personalized neoantigen vaccine in postoperative esophageal cancer.Methods Patients with stage IIA–IIIB ESCC (AJCC 8th) who received neoadjuvant platinum-based chemotherapy plus a PD-1 inhibitor, followed by radical resection and standard adjuvant therapy, were enrolled. Those without radiographic recurrence (RECIST v1.1) received iNeo-Vac-P01 (300 μg/peptide + GM-CSF 40 μg) subcutaneously on a multi-dose schedule. Primary endpoints were safety and 1-year recurrence-free survival (RFS). Secondary endpoints included RFS, overall survival (OS), and antigen-specific T-cell response.Results As of August 31, 2025, 27 patients were enrolled; 24 were evaluable for efficacy. All patients were male with ECOG 1; 58.3% (14/24) were aged ≥60 years. Most tumors were located in the mid-esophagus (58.3%, 14/24), and 66.7% (16/24) were ypT +N+ (indicating residual tumor and positive lymph nodes following neoadjuvant therapy). Treatment-related adverse events were primarily Grade 1-2, including fatigue (37.5%), fever (29.2%), and injection site reactions (erythema, pruritus, pain; 20.8%). One patient experienced Grade 3 acute hypersensitivity. With a median follow-up of 22.8 months, 95.8% completed 7 vaccinations. The 1-, 2-, and 3-year RFS rates were 91.3%, 83%, and 73.8%, respectively. The 1-, 2-, and 3-year OS rates were 100%, 94.7%, and 81.2%. These outcomes compare favorably with historical controls: the 3-year RFS rate of 73.8% in this study exceeds the 43% reported in CheckMate 577 (nivolumab) and 38.5% in a real-world PD-1-based adjuvant cohort. ELISpot analysis confirmed neoantigen-specific T-cell responses in all evaluated patients (24/24), with 78.5% (241/307) of vaccine peptides eliciting immune activation. Four patients showed 100% response rates, and two patients exhibited strong reactivity (>50 SFCs/2×105 PBMCs).Conclusions iNeo-Vac-P01 demonstrates promising efficacy in preventing recurrence and improving survival with a manageable safety profile in high-risk ESCC patients post-surgery. These results support the continued investigation of personalized neoantigen vaccines as adjuvant immunotherapy in esophageal cancer.Trial Registration Clinical Trial Registration: NCT05307835Ethics Approval Ethics approval was obtained from the ethics committees of The Second Affiliated Hospital of Zhejiang University School of Medicine. The ID of the approval is 2021-0997. Written informed consent was obtained from the patients before taking part.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.