A leucine derivate-adjuvanted LNP vaccine enhances antitumor immunity through mTOR activation and metabolic reprograming in dendritic cells

Neoantigen-derived peptide vaccines have been emergingly employed to treat tumors, however, their inefficient delivery and antigenicity remain challenging. In this study, for the first time a leucine derivate LLOMe (L-leucyl-l-leucine methyl ester) was repurposed to the adjuvant to reinforce the immune responses of lipid nanoparticle (LNP)-based peptide vaccine. Mechanistically, LLOMe disrupted the lysosomal entrapment of vaccine thus effectively enhanced bioavailability of antigens. Moreover, LLOMe in vaccine was found to stimulate the functional level of APCs via mTOR programed metabolism, while mTOR inhibitor rapamycin could abolish the adjuvating effect of LLOMe. In various animal tumor models receiving prophylactic or therapeutic vaccinations adjuvanted by LLOMe, the effective suppression of tumor growth was achieved through enhanced delivery of antigens and modulation of cellular immune responses. This study demonstrated that LLOMe-induced adjuvanticity significantly enhance the anti-tumor immunity of LNP vaccines, providing a clinically translational and potent adjuvant strategy for developing cancer vaccines.