Engineering Glycosidic Multivalent Platforms for Immune Modulation

This thesis explores innovative strategies for the development of carbohydrate-based cancer vaccines targeting tumor-associated carbohydrate antigens (TACAs), with a particular focus on MUC1 and Tn mimetics. Building on advances in glycoimmunology, the work integrates chemical design, synthetic methodology, and immunological evaluation to develop innovative and safer vaccine constructs capable of eliciting specific, antigen-driven immune responses. A comprehensive introduction outlines the molecular dialogue between cancer and the immune system, highlighting the challenges of immune recognition and evasion and the urgent need for innovative vaccine strategies. The work explores multiple delivery and presentation approaches: outer membrane vesicles (OMVs) are employed as highly immunogenic platforms with proven anticancer efficacy in vivo; TACA analogues are assembled into synthetic niosomal vesicles; and fully carbohydrate-based constructs using bacterial polysaccharides as carriers are designed to stimulate both antibody- and T cell–mediated responses. Additionally, a supramolecular strategy is investigated through the self-assembly of glycosylated peptide nanofibers, providing multivalent antigen presentation and a versatile platform to engage multiple arms of the immune system. Collectively, these approaches offer complementary and adaptable strategies to improve the specificity, potency, and effectiveness of next-generation cancer vaccines. Finally, the relationship between structural modifications of Tn mimetics and their biological interactions is examined. Changes in sulfur oxidation state are shown to modulate binding to macrophage galactose lectin (MGL) and inhibition of sialyltransferases, two molecular pathways acting in opposition within the tumor glycosylation landscape. Together, these studies provide mechanistic insight and establish a framework for the rational design of next-generation glycan-based cancer vaccines