Programming the immunological properties of mRNA vaccines for cancer.

Messenger RNA (mRNA) vaccines are a transformative platform for inducing antigen-specific T cell and B cell responses that are now being trialled in oncology. Here we propose an immunological framework that reconciles four axes controlling the efficacy of mRNA cancer vaccines: adjuvanticity versus immunopathology, antigen immunogenicity versus tolerance, adaptive immune memory versus exhaustion, and beneficial versus maladaptive trained immunity. We argue that mRNA vaccines should be viewed as programmable constructs in which nucleoside chemistry, delivery platforms and dosing schedules can be manipulated to tune these four axes by modulating antigen identity and decay, costimulation, cytokine tone and innate stimulation. By fitting recent mechanistic and translational insights into this framework, we outline design principles for positioning mRNA cancer vaccines within an optimal window of immune activation that supports durable, tumour-specific immunity while minimizing T cell exhaustion, tolerance and systemic toxicity.