TLR2 bridges innate and adaptive immunity, with agonists showing promise in vaccines and cancer therapy. In this study, we found natural product CaLGL-1, which functions as a "quiescent agonist" of TLR2, with its immunostimulatory potential masked by a labile acetal group. In an oxidative environment, CaLGL-1 is converted into potent TLR2 agonist. Inspired by this phenomenon, we rationally designed BXY-14, a derivative exhibiting cross-species TLR2 agonist activity. This compound demonstrates exceptional potency (THP-1 cells, EC50 = 2.2 nM; mBMDCs, EC50 = 1.8 nM), and functions as a superior vaccine adjuvant, eliciting stronger antibody responses than Diprovocim. Additionally, in murine models, BXY-14 markedly downregulated intratumoral PD-L1 expression and demonstrated synergistic efficacy with the anti-PD-L1 monoclonal antibody atezolizumab, resulting in significantly prolonged overall survival. Together, this work establishes metabolically gated immunity and delivers a translational TLR2 agonist bridging bacterial metabolite chemistry with immunotherapy.
Jia et al. (Sun,) studied this question.