Licensed and investigational TLR4 agonists as vaccine adjuvants: structural basis, clinical progress, and future directions.

The development of innovative vaccine platforms, including protein subunit and nucleic acid vaccines, has advanced rapidly and established new technical paradigms for infectious disease prophylaxis. Nonetheless, many next-generation vaccines display suboptimal intrinsic immunogenicity owing to restricted antigenic complexity, resulting in inadequate protective immunity when delivered without adjuvants. Aluminum-containing adjuvants, the most widely deployed clinical adjuvants, primarily potentiate humoral immunity but elicit modest cellular immune responses, thereby failing to satisfy the immunological demands of modern vaccine platforms. Moreover, standard vaccines often fail to confer robust protective immunity in immunocompromised individuals. Accordingly, the rational design and development of next-generation vaccine adjuvants are critical to expanding the clinical translation of innovative vaccines and enhancing immunogenicity in vulnerable populations. In recent years, multiple novel adjuvants have gained clinical approval; of these, Toll-like receptor 4 (TLR4) agonists-core immunostimulatory components of several licensed adjuvant systems-have exhibited potent immunomodulatory activity across diverse infectious disease indications. This review offers a comprehensive synthesis of contemporary TLR4-targeted adjuvants, emphasizing their evolutionary development, molecular mechanisms of action, and clinical translational landscape. We aim to furnish mechanistic insights and translational guidance for scientists optimizing current adjuvants and discovering new TLR4-based candidates.