Progress on therapeutic mRNA vaccines for cancer

Abstract

Therapeutic mRNA vaccines are a clinically validated cancer immunotherapy platform using in vitro transcribed mRNA encoding tumor antigens to induce durable anti-tumor immunity. Advances in mRNA engineering, lipid nanoparticle (LNP) delivery, and immunomodulatory combinations have propelled this approach from preclinical models to randomized trials with survival benefit. This review systematically examines vaccine efficacy through an antigen–delivery–immunomodulation tripartite framework. We trace the evolution from shared tumor-associated antigens to personalized neoantigens identified by computational pipelines, discuss ionizable lipid chemistry and LNP formulation for controlled tissue tropism and transfection, and analyze the bidirectional crosstalk between vaccine components and innate immune sensing that shapes adaptive T cell responses. Clinical evidence across melanoma, pancreatic cancer, non-small cell lung cancer, and other solid tumors is critically evaluated, alongside combination strategies—checkpoint blockade, oncolytic virotherapy, and adoptive cell therapy to overcome TME resistance. Persistent challenges include optimal neoantigen selection, standardized immune monitoring, and predictive biomarkers. We conclude that future research should prioritize systematic optimization of the tripartite design through multi-antigen targeting, tissue-specific delivery engineering, and rational combination immunotherapy, aiming to establish mRNA cancer vaccines as a standard-of-care modality.