Self-Cooperative RNA Vaccine Mitigates Dendritic Cell-Mediated Acquired Immune Resistance to Potentiate Cell Therapy for Solid Tumors.

Conventional mRNA cancer vaccines are designed to maximize antigen potency but often overlook vaccination-induced immune resistance. In this study, we identified a negative immune regulatory mechanism, whereby mRNA vaccination induces programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) through type I interferon (IFN-I) signaling. Elevated PD-L1 expression impairs T-cell priming in lymph nodes through engagement of programmed death receptor 1 (PD-1) on T lymphocytes. To address this challenge, we developed a self-cooperative RNA vaccine (SCORV) strategy by co-delivering antigen-encoding RNA and small interfering RNA against PD-L1 (siPD-L1) within a single lipid nanoparticle (LNP). Through iterative screening of >300 ionizable lipids, we optimized a DC-targeted LNP formulation with high RNA delivery efficiency and minimal immunotoxicity. SCORV simultaneously suppresses PD-L1-mediated immune resistance during antigen presentation and enhances T cell priming while alleviating T cell exhaustion. Importantly, SCORV potentiates the tumor reactivity of adoptively transferred tumor-infiltrating lymphocytes and elicits robust antitumor immunity in murine melanoma and hepatocellular carcinoma models. This work highlights a rational design principle for mRNA vaccines that self-correct vaccination-induced immune resistance.