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

ABSTRACT

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.