A Platinum(IV) Metallo‐Stapling Approach to Tumor‐Specific Prodrugs for Targeted Chemo‐Immunometabolic Cancer Therapy

The clinical utility of classical metallodrugs is limited by insufficient tumor selectivity and systemic toxicity. Platinum-based chemotherapeutics, while foundational in oncology, exemplify this challenge because of their indiscriminate action on both cancerous and healthy cells, leading to detrimental side effects. Inspired by the versatile coordination chemistry in metalloproteins, we developed a platinum(IV)-based metallo-stapling strategy to construct tumor-specific metalloprodrugs. This approach leverages the Pt(IV) complex dually as a chemotherapeutic agent and a structural staple that conformationally rigidifies an epidermal growth factor receptor (EGFR)-targeting ligand. The resultant macrocyclic metalloprodrug exhibits precise targeting of EGFR-overexpressing malignancies, achieving in vivo tumor platinum accumulation 7-fold higher than the parent Pt(II) complex and 5-fold greater than its linear counterpart due to superior metabolic stability and efficient receptor-mediated uptake conferred by the macrocyclic architecture. Upon reaching the tumor microenvironment, the construct undergoes dual-payload release to liberate platinum drug and the IDO-1 inhibitor NLG919 analogue (NLG), eliciting a robust immunogenic cell death cascade while simultaneously reversing immunosuppression. Furthermore, a combination with an aPD-L1 immune checkpoint blockade produces a marked synergistic antitumor response. This work establishes Pt(IV)-directed metallo-stapling as a versatile platform for precision cancer therapy, offering a generalizable strategy to chemically engineer a broad range of metalloprodrugs with enhanced tumor selectivity and biosafety.