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.