Neoantigen evolution in cancer: immunoediting, immune escape, and future vaccine strategies

Cancer immunotherapy has changed cancer treatment, with neoantigen-based vaccines emerging as a promising strategy to induce tumor-specific immune responses while minimizing adverse effects on healthy tissues. Advances in next-generation sequencing, immunopeptidomics, artificial intelligence, and computational prediction have accelerated the identification of patient-specific neoantigens and enabled the development of personalized cancer vaccines. Despite encouraging safety profiles and robust induction of neoantigen-specific T-cell responses, clinical efficacy has remained inconsistent. Tumor evolution driven by genomic instability continuously reshapes the neoantigen landscape through intratumoral heterogeneity, immune-mediated selection, and antigen gain or loss, facilitating immune escape and limiting durable therapeutic responses. In addition, T-cell dysfunction and the immunosuppressive tumor microenvironment further compromise vaccine efficacy. In this review, we discuss the origin and diversity of tumor antigens, recent advances in neoantigen identification and vaccine development, and the biological mechanisms that constrain the clinical success of personalized cancer vaccines. We summarize evidence from clinical trials that highlights both the promise and the current limitations of neoantigen-based immunotherapy, and discuss the importance of incorporating tumor evolution into vaccine design. Finally, we present Variable Epitope Libraries (VELs), a vaccine strategy that uses immunogens based on combinatorial libraries of highly mutated epitope variants designed to broaden immune recognition, reduce immune escape, and improve the durability and effectiveness of cancer immunotherapy.