Gastrointestinal (GI) cancers remain a major cause of cancer-related morbidity and mortality. Immunotherapeutic approaches have improved outcomes in selected settings; however, their efficacy in GI malignancies is often constrained by tumor heterogeneity and an immunosuppressive tumor microenvironment. mRNA-based vaccines have emerged as a distinct immunotherapeutic platform, characterized by rapid and cell-free manufacturing, modular antigen design, and the capacity for patient-specific neoantigen targeting. These features differentiate mRNA vaccines from conventional protein-based vaccines, viral vectors, and ex vivo cell-based approaches. This review critically examines the biological rationale and translational landscape of mRNA vaccines in GI cancers. We discuss the mechanistic principles underlying antigen expression and immune activation across conventional, self-amplifying, and trans-amplifying mRNA platforms. Particular emphasis is placed on antigen selection strategies, including tumor-associated antigens and personalized neoantigens, and their implications for immune specificity and therapeutic variability. We further analyze key barriers to clinical efficacy, including inefficient antigen presentation, stromal and immune-mediated resistance within the tumor microenvironment, and challenges in delivery, stability, and large-scale manufacturing. Clinical trials data demonstrate that mRNA vaccines can induce measurable antigen-specific immune responses, while translation into durable clinical benefit is the major barrier. Accordingly, emerging strategies increasingly focus on rational combination approaches, including immune checkpoint inhibition, modulation of tumor-associated macrophages, and perioperative immune intervention. Overall, mRNA vaccines represent a flexible but still evolving platform in GI oncology. Their future clinical impact would depend on improved patient stratification, optimization of delivery systems, and integration with therapies that address tumor-intrinsic and microenvironmental resistance mechanisms.
