Engineering Universal Cancer Immunity: Non-Tumor-Specific mRNA Vaccines Trigger Epitope Spreading in Cold Tumors

The landscape of cancer immunotherapy must shift from personalized neoantigen vaccines toward universal platforms that leverage innate immune activation. This review examines a novel mRNA vaccine strategy that encodes non-tumor-specific antigens, carefully selected pathogen-derived or synthetic sequences designed to transform immunologically “cold” tumors into inflamed therapy-responsive microenvironments. Unlike conventional approaches requiring patient-specific tumor sequencing and 8–12-week manufacturing timelines, this platform utilizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to trigger broad innate immune activation through multiple pattern recognition receptors (PRRs). The key therapeutic mechanism is epitope spreading, where vaccine-induced inflammation reveals previously hidden tumor antigens, enabling the immune system to mount responses against cancer-specific targets without prior knowledge of these antigens. Delivered via optimized lipid nanoparticles (LNPs) or alternative polymer-based systems, these vaccines induce epitope spreading, enhance checkpoint inhibitor responsiveness, and establish durable antitumor memory. This approach offers several potential advantages, including immediate treatment availability, a cost reduction of up to 100-fold compared to personalized vaccines, scalability for global deployment, and efficacy across diverse tumor types. However, risks such as cytokine release syndrome (CRS), potential for off-target autoimmunity, and challenges with pre-existing immunity must be addressed. By eliminating barriers of time, cost, and infrastructure, this universal platform could help democratize access to advanced cancer treatment, potentially benefiting the 70% of cancer patients in low- and middle-income countries (LMICs) who currently lack immunotherapy options.