Neoantigen mRNA vaccines and A₂A receptor antagonism: A strategy to enhance T cell immunity

Although neo-antigen mRNA vaccines are promising for personalized cancer therapy, their effectiveness is often limited by the immunosuppressive tumor microenvironment (TME). The adenosine A₂A receptor (A₂AR) inhibits dendritic cell (DC) function and weakens antitumor T cell responses through hypoxia-driven mechanisms within the TME. This review explores a novel strategy combining neo-antigen mRNA vaccines with A₂AR antagonists (A₂ARi). By targeting A₂AR, this approach reduces TME-induced immunosuppression, enhances DC activation, and improves neo-antigen presentation. The review also discusses lipid nanoparticles (LNPs) to co-deliver A₂ARi and mRNA vaccines, optimizing their effectiveness. The integration of neo-antigen mRNA-LNPs with A₂ARi modulation offers a promising strategy to overcome immunosuppression, stimulate DC activation, and achieve precise anti-tumor responses with minimal off-target effects. This synergy represents significant progress in cancer immunotherapy, advancing the potential for personalized neoantigen therapies.