Improved Systemic Immunochemotherapy Employing an Oxaliplatin‐TLR7/8 Agonist Prodrug Strategy

ABSTRACT Systemic application of Toll‐like receptor 7/8 (TLR7/8) agonists against cancer is severely limited due to uncontrolled immune activation. In this study, a platinum(IV)‐based prodrug strategy is developed for the systemic administration of a TLR7/8 agonist, selectively activated in the malignant tissue simultaneously with the immunogenic cell death inducer oxaliplatin. Two oxaliplatin(IV)‐based complexes are synthesized comprising the TLR7/8 agonist gardiquimod: Ox‐Gardi‐PEG, containing polyethylene glycol as the second axial ligand, and Ox‐Gardi‐Mal, a maleimide‐bearing derivative to exploit the tumor‐targeting effects of serum albumin. In vitro, cytotoxicity and immune pathway‐inducing potency of Ox‐Gardi‐PEG and Ox‐Gardi‐Mal are diminished under standard cell culture conditions compared to free oxaliplatin and gardiquimod, respectively, and markedly enhanced under reducing conditions, underscoring the activation‐by‐reduction concept. In vivo, Ox‐Gardi‐Mal shows superior and TLR7/8 signaling‐dependent anticancer efficacy and prolongs overall survival of cancer‐bearing mice, while mitigating hematotoxic effects associated with oxaliplatin. Therapy significantly elevates expression of MHC‐I on antigen‐presenting immune cell subsets, increases the frequency of activated plasmacytoid dendritic cells and tumor‐infiltrating CD8 + T cells, as well as depleted primarily immunosuppressive M2 macrophages. These results demonstrate that tumor‐targeted oxaliplatin(IV)‐based prodrugs carrying TLR7/8 agonists offer a potent dual‐release strategy for improved immunochemotherapy, while minimizing excessive immune responses associated with systemic TLR7/8 activation.