An Enhanced Cancer Immunogenic Cell Death Strategy: Fibrate-Oxaliplatin(IV) Conjugates with Modulating Tumor Immune Microenvironment

The present immunogenic cell death (ICD) strategies remain far from being suitable for effective clinical applications, highlighting the urgent need for novel strategies. Herein, the oxaliplatin-like fibrate-derived platinum(IV) conjugates <b>2</b>-<b>7</b> were designed and synthesized to explore novel approaches for enhancing ICD via modulation of tumor microenvironment (TME). Bioactivity evaluations showed that these conjugates accumulated highly in cells and released active components, exerting cytotoxicity. Especially, <b>5</b> exhibited 319-fold higher cytotoxicity than oxaliplatin. Mechanistic studies revealed that these conjugates induced severe DNA damage, mitochondrial dysfunction, and endoplasmic reticulum stress, ultimately activating the apoptotic pathway. Importantly, these events interacted with cholesterol metabolic regulation to form a self-amplifying cycle, which substantially enhanced damage-associated molecular pattern release to strengthen ICD and further modulated the TME by promoting CD8⁺ T cell infiltration and cytokine secretion while downregulating PD-L1 expression and Treg-mediated immunosuppression. <i>In vivo</i>, these conjugates exhibited favorable biocompatibility, potent antitumor activity and reduced toxicity compared to oxaliplatin.