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In this study, a platinum(IV)\u2010based 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)\u2010based complexes are synthesized comprising the TLR7\/8 agonist gardiquimod: Ox\u2010Gardi\u2010PEG, containing polyethylene glycol as the second axial ligand, and Ox\u2010Gardi\u2010Mal, a maleimide\u2010bearing derivative to exploit the tumor\u2010targeting effects of serum albumin. In vitro, cytotoxicity and immune pathway\u2010inducing potency of Ox\u2010Gardi\u2010PEG and Ox\u2010Gardi\u2010Mal are diminished under standard cell culture conditions compared to free oxaliplatin and gardiquimod, respectively, and markedly enhanced under reducing conditions, underscoring the activation\u2010by\u2010reduction concept. In vivo, Ox\u2010Gardi\u2010Mal shows superior and TLR7\/8 signaling\u2010dependent anticancer efficacy and prolongs overall survival of cancer\u2010bearing mice, while mitigating hematotoxic effects associated with oxaliplatin. Therapy significantly elevates expression of MHC\u2010I on antigen\u2010presenting immune cell subsets, increases the frequency of activated plasmacytoid dendritic cells and tumor\u2010infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, as well as depleted primarily immunosuppressive M2 macrophages. These results demonstrate that tumor\u2010targeted oxaliplatin(IV)\u2010based prodrugs carrying TLR7\/8 agonists offer a potent dual\u2010release strategy for improved immunochemotherapy, while minimizing excessive immune responses associated with systemic TLR7\/8 activation.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514588","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T10:00:53Z","timestamp":1776074453000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Improved Systemic Immunochemotherapy Employing an Oxaliplatin\u2010TLR7\/8 Agonist Prodrug Strategy"],"prefix":"10.1002","volume":"13","author":[{"given":"Michael","family":"Gutmann","sequence":"first","affiliation":[{"name":"Medical University of Vienna Center for Cancer Research  Vienna Austria"},{"name":"Comprehensive Cancer Center Vienna Medical University &amp; General Hospital  Vienna 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