mRNA-Based Vaccination Drives in Vivo Dendritic Cell Reprogramming and Selective Cytotoxic T Lymphocyte Modulation for Enhanced Antitumor Immunity.

Abstract

Precisely engineering T cells for targeted tumor recognition and overcoming the insufficiency of antigen-specific T cells in vivo are major challenges in cancer immunotherapy. Here, we present a streamlined strategy termed VISIT (<u>v</u>accine-<u>i</u>nitiated <u>s</u>elect<u>i</u>ve <u>T</u> cell modulation) that enables spatiotemporal modulation of cytotoxic T lymphocytes (CTLs) through in vivo dendritic cell (DC) reprogramming. This approach employs optimized lipid nanoparticles to preferentially deliver mRNAs to splenic DCs, enabling the simultaneous presentation of tumor antigens and the membrane-bound IL-15/IL-15Rα complex as a T cell booster on the DC surface, thereby promoting antigen-specific CTL activation and expansion while minimizing nonspecific immune activation. Prophylactic vaccination resulted in complete tumor rejection and the establishment of long-term immunological memory, providing effective protection against tumor rechallenge. In mice with established OVA expressing colon carcinoma and aggressive melanoma models, systemic vaccination maximized antigen-specific CTL responses and inhibited tumor growth. When combined with immune checkpoint inhibitors, the treatment exhibited a synergistic effect, further extending overall survival in melanoma-bearing mice. Overall, the VISIT vaccination platform offers an in vivo DC reprogramming approach for developing personalized cancer immunotherapies through precise spatiotemporal modulation of DC-T cell interactions.