An epitope-directed mRNA vaccine inhibits tumor metastasis through the blockade of MICA/B α1/2 shedding

Antigenic peptide-based mRNA vaccines have been explored for immunotherapeutic use in various types of cancer because of their advantages in activating durable and specific immune responses. However, their role in modulating tumor metastasis is still unclear. Here, we identify a conserved linear epitope-based peptide, Ma3P, located in the proteolytic region of major histocompatibility complex (MHC) class I-related chain A (MICA) α3 and further design mCM10-L, an mRNA vaccine that encodes the carrier protein CRM197 and 10 tandem repeats of Ma3P. We demonstrate that vaccination with mCM10-L induces the production of specific antibodies that block MICA/B α1/2 shedding, activate CD8⁺ T cells and natural killer (NK) cells, and significantly inhibit MICA/B⁺ tumor metastasis in mice. Furthermore, mCM10-L stimulation triggers the production of specific antibodies to promote MICA/B-mediated immune killing in an in-vitro-interacting human organoid model and humanized mice. Our results indicate the potential clinical application prospects of the mCM10-L vaccine.