A Multiple Enzyme‐Mimetic Platinum–Ruthenium Nanohybrid Prodrug Potentiates Chemo‐/Chemodynamic‐/Immuno‐Therapy of Hypoxic Tumors

ABSTRACT Hypoxia in the tumor microenvironment (TME) is a hallmark of solid tumors and is tightly associated with the development of chemoresistance and immunosuppression, severely compromising the efficacy of mainstream clinical oncological treatments. Platinum‐based metallodrugs, especially oxaliplatin (Oxa), serve as first‐line chemotherapeutics in clinical practice. However, their clinical utility is greatly restricted by acquired drug resistance, insufficient tumor accumulation, and weak immunostimulatory capacity. Herein, we synthesize a platinum–ruthenium nanohybrid prodrug (denoted as PR) via self‐assembly, which integrates Oxa PR and ruthenium ions for synergistic chemo‐/chemodynamic‐/immunotherapy of hypoxic tumors. The PR nanohybrid possesses intrinsic multi‐enzyme activities (catalase, peroxidase, and glutathione peroxidase), enabling efficient oxygen generation, hydroxyl radical production, and glutathione depletion. These cascading events enhance chemosensitivity, trigger robust immunogenic cell death, and activate the cGAS‐STING signaling pathway. Furthermore, nanocatalytic modulation of the hypoxic TME alleviates hypoxia‐driven immunosuppression, downregulates PD‐L1 expression on cancer cells, and reinforces antitumor immune responses. In vitro and in vivo investigations demonstrate that PR nanohybrid exhibits superior anticancer efficacy over free Oxa and displays promising potential in combination with PD‐1 blockade therapy. These findings highlight the PR nanohybrid as a versatile TME‐modulating platform for hypoxic tumor treatment, offering a novel strategy to advance platinum‐based combination cancer therapy.