Neoantigen-Encoded Oncolytic Viruses as Personalized Cancer Vaccines

Neoantigen vaccines have revitalized cancer vaccination by targeting tumor-specific mutant epitopes largely absent from central tolerance. Yet, clinical benefits remain inconsistent, in part because conventional vaccine platforms often do not reliably deliver antigens within an inflammatory tumor context, struggle to overcome immunosuppressive tumor microenvironments, and may not rapidly adapt to tumor heterogeneity and evolution. Oncolytic viruses (OVs) provide a mechanistically distinct route to "vaccinate in situ" by coupling tumor-selective infection and immunogenic cancer cell death with local innate immune activation, antigen release, and remodeling of the tumor microenvironment. In parallel, advances in sequencing, neoantigen prediction (e.g., updated NetMHCpan and MHCflurry tools as of 2025), and antigen presentation validation have enabled rational selection of patient-specific targets. At the same time, modern OV engineering supports insertion of neoantigen payloads and immune-modulatory transgenes. Here, we summarized principles that underpin neoantigen-encoded OVs as personalized cancer vaccines, emphasizing how OV adjuvanticity and antigenicity interact to drive priming, epitope spreading, and durable systemic immunity. We discussed major OV platforms with respect to payload capacity, expression control, manufacturability, and clinical track records, including lessons learned from approved or late-stage OVs such as talimogene laherparepvec (T-VEC) and teserpaturev/G47Δ. We also discussed design choices for encoding neoantigens (polyepitope strings, minigenes, long peptides; class I/II balancing), prioritizing translational biomarkers and immune-monitoring strategies, and outlining regulatory and GMP considerations for "platform-plus-variable insert" products. Finally, we propose a pragmatic clinical workflow for rapid personalization to maximize therapeutic index. Tightly integrating neoantigen science with immunovirotherapy, including recent 2025 preclinical advances like oncolytic adenovirus neoantigen delivery sensitizing low-TMB tumors to PD-1 blockade, could enable next-generation personalized cancer vaccines capable of converting "cold" tumors into responsive, systemically controlled disease.