Clinically, there are very few prophylactic therapies available to prevent recurrence in patients with hepatocellular carcinoma (HCC) following curative resection. Although neoantigen-based vaccines have shown the capacity to provoke strong antitumor immunity across multiple solid malignancies, their ability to trigger such immunity in HCC—and to act as a safe, efficacious prophylactic measure against postoperative recurrence—remains poorly understood. A customized neoantigen vaccine was developed and delivered to 10 high-risk HCC patients in a prime-boost regimen. Safety and immunological reactivity were monitored through adverse event recording, tissue sequencing, ELISpot assays, and T-cell receptor sequencing. Clinical outcomes were measured by recurrence-free survival (RFS) and patient-specific circulating tumor DNA (ctDNA) analysis. None of the 10 patients experienced notable adverse effects during vaccination. By the trial’s data cutoff, imaging confirmed recurrence in 8 patients, whereas 2 remained free of relapse. The median RFS from the initial vaccination across all 10 patients was 7.4 months. Among the 7 patients who received the full vaccination schedule, 5 displayed detectable neoantigen-specific T-cell responses and achieved markedly prolonged RFS after surgery compared with the remaining 5 patients (lacking responsive neoantigens or receiving only the prime dose) and propensity score-matched controls (p = 0.035). Additionally, serial detection of patient-specific neoantigen mutations in ctDNA allowed real-time monitoring of treatment response and disease status during vaccination and subsequent follow-up. This study establishes personalized neoantigen vaccination as a safe, practical, and promising approach for preventing HCC recurrence. Disease dynamics can be accurately tracked via neoantigen mutation signatures in ctDNA, offering valuable insights for tailored management of HCC patients.
