Self-Boosting RNA Vaccine Reduces Immune Resistance by Dendritic Cells to Improve Cell Therapy for Solid Tumors

mRNA vaccination induces programmed death-ligand 1 (PD-L1) expression in dendritic cells, which may impair T-cell priming.

• The negative immune regulatory mechanism involves type I interferon signaling leading to increased PD-L1 expression.
• Elevated PD-L1 levels hinder T-cell activation by interacting with PD-1 on T lymphocytes in lymph nodes.
• A self-cooperative RNA vaccine strategy was developed to co-deliver antigen-encoding RNA and small interfering RNA against PD-L1.
• An optimized lipid nanoparticle formulation was achieved with high RNA delivery efficiency and low immunotoxicity.
• This approach enhances T-cell priming and reduces T-cell exhaustion while counteracting PD-L1-mediated immune resistance.
• The strategy demonstrated improved antitumor immunity in mouse models of melanoma and liver cancer.

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