Molecular origin, discovery, validation and application of neoantigens

Neoantigens, tumor-specific peptides originating from somatic mutations, are pivotal targets for personalized cancer immunotherapy. This review synthesizes current neoantigen research, encompassing its molecular origins, discovery methodologies, validation strategies and translational applications. We emphasize integrated genomics, mass spectrometry-based immunopeptidomics and machine learning-enhanced bioinformatics pipelines that are concurrently used to predict neoantigen processing, major histocompatibility complex (MHC)-binding affinity, and immunogenicity. Neoantigen-targeted vaccines demonstrate promising efficacy in solid tumors while combinatorial approaches integrating neoantigen-directed therapies with other immunotherapeutics show significant potential to overcome tumor immune evasion mechanisms and improve treatment outcomes. These new progresses underscore the critical role of neoantigens in advancing precision cancer immunotherapy.