Mechanistic biomarkers for cancer vaccine development: from cancer cell biology to neoantigen-guided precision immunotherapy.

Cancer vaccines have resurged in oncology because they address a central question in precision medicine: whether the molecular identity of a tumor can be converted into an immune target that is both specific and clinically useful. Preventive vaccines against oncogenic viruses have already shown that immune intervention can reduce the burden of virus-associated cancers. Therapeutic cancer vaccines face a more difficult task, because established tumors arise from self-tissues, change over time, and often acquire mechanisms that limit antigen presentation, T-cell entry, or immune-mediated killing. This review examines cancer vaccines as biomarker-driven tools within precision oncology. The focus is not only on vaccine platforms, but on the biological requirements that make an antigen suitable for therapeutic targeting. Tumor-specific mutations, viral antigens, recurrent driver alterations, frameshift peptides, cancer-testis antigens, and personalized neoantigens may all provide vaccine targets, but their presence alone is not enough. A clinically relevant vaccine antigen should be expressed by tumor cells, processed and presented through HLA molecules, recognized by functional T cells, and sufficiently retained during tumor evolution. This distinction is particularly important because sequencing and computational prediction now generate many candidate neoantigens whose immunological relevance still requires experimental confirmation. Particular attention is given to antigen-presentation defects, clonal and subclonal heterogeneity, tumor microenvironment barriers, circulating tumor DNA-defined minimal residual disease, and immune-response monitoring. Colorectal cancer is used as a working model because microsatellite instability-high/mismatch repair-deficient tumors, microsatellite-stable tumors with immune-resistant features, and recurrent alterations in MMR genes, KRAS, BRAF, adenomatous polyposis coli, and TP53 illustrate how cancer-cell signaling, neoantigen generation, tumor microenvironment remodeling, and patient stratification intersect. Overall, cancer vaccines are unlikely to become universal stand-alone treatments for advanced solid tumors. Their most credible role may emerge in molecularly selected patients, adjuvant therapy, minimal residual disease, virus-associated malignancies, and rational combinations with checkpoint inhibitors or tumor microenvironment-modulating agents.