A Chemically Defined Four-Component Self-Adjuvanting Tn Vaccine Activating Mincle, FcγR, and CD206 for Enhanced Antitumor Immunity.

Tumor-associated carbohydrate antigens (TACAs), such as the Tn antigen, are promising targets for cancer vaccines but are limited by their low immunogenicity and a lack of T-cell responses. Traditional carrier-protein conjugates often encounter issues such as epitope suppression and heterogeneous formulations. Herein, we present the design, synthesis, and immunological evaluation of a chemically defined, four-component self-adjuvanting glycoconjugate. This molecule combines multiple innate immune activation strategies into a single, unimolecular framework, incorporating (1) a synthetic Tn as the B-cell epitope; (2) vizantin, a strong Mincle agonist, as an internal adjuvant; (3) rhamnose to attract endogenous antibodies for Fcγ receptor-mediated uptake; and (4) mannose to target dendritic cells through CD206. By ensuring precise co-delivery and synergistic activation of Mincle, Fcγ receptor, and CD206 pathways, this construct induces strong IgG switching, Th1‑type cytokine responses, and significant tumor suppression in mice. This research offers a versatile chemical approach for next‑generation TACA vaccines, illustrating how activating multiple innate pathways can overcome the longstanding limitations of carbohydrate-based immunotherapies.