Lessons from mycobacteria: development and design of Mincle-targeting adjuvants

Host defense against intracellular pathogens, including viruses and mycobacteria, requires not only antibody production but also T cell-mediated cellular immunity, which is often overlooked in current vaccine strategies. C-type lectin receptors (CLRs) are one of the innate immune receptors that can promote adaptive immunity through the induction of co-stimulatory molecules or soluble factors in antigen-presenting cells. This review focuses on the potential of CLR ligands, specifically those for macrophage-inducible C-type lectin (Mincle), as next-generation vaccine adjuvants. Mincle recognizes glycolipids such as trehalose dimycolate (TDM) from mycobacteria and induces Th1 and Th17 responses, crucial mechanisms for countering intracellular pathogens. We discuss the structural basis of the ligand-recognition modes of Mincle, which involves both sugar-binding pockets and hydrophobic grooves to accommodate acyl chains. Additionally, we discuss efforts to develop synthesizable and highly active ligands such as trehalose dibehenate (TDB) and lipidated brartemicin (C18Brar). We further highlight novel strategies to enhance immunostimulatory efficacy, including the concept of dual-ligand adjuvants (e.g. C18Brar-muramyl dipeptide conjugate) and the use of nanoparticle/liposome delivery systems (e.g. CAF formulations). Collectively, these advancements highlight the potential of Mincle ligands as candidates for effective adjuvants. For clinical application, species-specific differences in adjuvant effectiveness between humans and experimental animals must be addressed, and highly functionalized Mincle ligands must be developed. Future research should establish Mincle-targeting ligands as indispensable tools for the development of next-generation vaccines.