Abstract

mRNA cancer vaccines demonstrate potential in clinical trials, but existing platforms struggle to boost antitumor efficacy without added cost or complexity. Here, we present a streamlined linear cap-independent mRNA (LciRNA) cancer vaccine platform, achieved by fusing a UPA protective sequence, composed of a viral exoribonuclease-resistant RNA (xrRNA) and a poly(A) binding protein (PABP) motif, to an optimized Enterovirus A internal ribosome entry site. UPA impedes exonuclease-mediated decay and recruits RNA-binding proteins to stabilize LciRNA, enabling stable in vivo expression without 5’ capping or modifications. Moreover, LciRNA innately stimulates immune responses by engaging pattern-recognition receptors, promoting dendritic cell maturation, and upregulating proinflammatory signals. In murine melanoma and HPV-associated tumor models, this vaccine platform elicits strong systemic and intra-tumoral T cell responses, achieving superior tumor control, demonstrating how immune stimulation-translation synergy underpins its efficacy. Thus, we present a cost-effective platform with enhanced efficacy, and highlight coupled immune stimulation and translation as a paradigm for future mRNA cancer vaccines.