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To evaluate the potential impact of epitope-flanking sequences, we compared the immunogenicity of two mRNA vaccines in the MC38 mouse model. Both vaccines coded for the same tumor-specific antigens (TSAs). The only difference between the two vaccines was the identity of the epitope-flanking amino acids. The vaccine encoding TSAs bordered by optimized flanking sequences (TSA-Opti) cleared established tumors and elicited robust CD8+ T-cell responses. In contrast, the vaccine encoding the same TSAs surrounded by natural flanking sequences (TSA-Nat) induced weaker responses and incomplete protection against tumor growth. Quantitative immunopeptidomics showed that TSA-Opti increased antigen presentation levels, providing a mechanistic link between flanking-sequence design and the enhanced magnitude, clonal diversity, and functionality of TSA-specific CD8+ T cells. TSA-Opti further promoted durable memory, conferring long-term protection against tumor rechallenge. These results identify epitope-flanking sequences as tunable design elements that control peptide\u2013MHC I density and thereby shape the magnitude, clonal diversity, tissue localization, and durability of antitumor CD8+ T-cell immunity.<\/jats:p>","DOI":"10.3390\/cells15191753","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T08:18:46Z","timestamp":1790583526000},"page":"1753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimized Epitope-Flanking Sequences Enhance Antigen Presentation and T-Cell Responses Following mRNA Vaccination"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1316-6483","authenticated-orcid":false,"given":"Marie-Pierre","family":"Hardy","sequence":"first","affiliation":[{"name":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3T 1J4, 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