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Immunization is a promising strategy to activate these T cell populations. To our knowledge, immunization with messenger RNA (mRNA) and the iNKT agonist, \u03b1-galactosylceramide (\u03b1GC), has not been studied in MM, as knowledge on clinically relevant antigens in preclinical MM models is lacking.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Microarray data and immunopeptidomics (imPep) were used to identify candidate antigens for immunization in 5TMM models. Galsomes, lipid nanoparticles containing antigen mRNA and \u03b1GC were used to immunize 5T33MM-bearing mice. This treatment was combined with a CD40 agonist. Tumor burden and activation of iNKT cells and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells were studied using M-protein electrophoresis, flow cytometry and ELISA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RNA transcripts revealed survivin as a candidate antigen. Prime-boost Galsomes therapy targeting survivin significantly reduced M-protein levels despite low survivin-specific T cell responses. Further analysis showed potential T cell fratricide. ImPep revealed HSP60, Idiotype, PICALM and EF1A1 as candidate antigens. Prime-boost therapy with Galsomes targeting these antigens reduced MM growth significantly when combined with a CD40 agonist, coinciding with significantly improved antigen presentation, costimulation and cytotoxicity of iNKT cells and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings highlight the potential of Galsomes, an mRNA vaccine designed to activate CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and iNKT cells, for MM therapy, and emphasize the importance of combinatorial approaches, addressing immune anergy for effective MM immunotherapies.\n                    <\/jats:p>\n                  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