Neoantigen cancer vaccines in the mRNA Era: antigen selection, platform engineering, and clinical translation.
Neoantigen vaccines have become a central direction in precision cancer immunotherapy because they aim to target tumor-specific peptide sequences generated by somatic alterations rather than self-antigens shared with normal tissues. This biological distinction reduces the barrier of central tolerance and creates a rational basis for individualized T-cell priming. The field has also changed technically. Tumor-normal sequencing, transcriptomic filtering, HLA typing, immunopeptidomics, and algorithmic prioritization now make it possible to move from a patient tumor sample to a ranked set of candidate vaccine targets within a clinically meaningful interval. Because durable vaccine responses frequently depend on CD4-positive T-cell help, we also give explicit attention to HLA class II prediction, which remains substantially less accurate than class I prediction. Among available delivery formats, mRNA platforms have become especially important because they can encode multiple patient-specific epitopes in a single product and can be redesigned rapidly as prediction and delivery methods improve, although synthetic long peptide, dendritic cell, viral vector, and DNA platforms retain specific advantages that we compare directly. This review re-examines neoantigen vaccines as a translational system rather than as a single technology. We first outline the biological basis of neoantigen recognition and classify the major antigen sources. We then discuss target discovery, HLA-restricted presentation, computational ranking, immunopeptidomic evidence, and functional validation. Next, we compare vaccine platforms, with particular emphasis on why personalized mRNA vaccines now dominate late-stage clinical development. Finally, we analyze current clinical evidence in melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, glioblastoma, and other solid tumors-reporting primary efficacy endpoints, hazard ratios, patient numbers, and follow-up durations where available-and we identify the main barriers that still prevent broad clinical implementation. In our assessment-offered as an expert interpretation rather than as a conclusion derived from comparative or pooled analyses, because the supporting evidence still rests largely on single-arm and early-phase trials in heterogeneous tumor types-the strongest current signal supports use in adjuvant, perioperative, and minimal residual disease settings, usually in combination with checkpoint blockade or other immune-modifying strategies. Neoantigen vaccination is unlikely to become a universal standalone therapy. Its more realistic value is as a programmable immune-priming component within precision oncology.