Metal-Based Combination Therapies in Cancer: Mechanistic Principles and Emerging Opportunities

Metal-based anticancer agents occupy a distinctive niche in cancer therapy owing to their exceptional coordination versatility, redox activity, and tunable photochemical properties, which enable simultaneous engagement of multiple cellular pathways. Despite the clinical success of platinum-based chemotherapy, metal-based monotherapy is frequently hindered by resistance development, dose-limiting toxicity, and incomplete tumor control. Combination therapy has therefore emerged as an indispensable approach in clinical oncology, offering synergistic enhancement of antitumor efficacy, mitigation of resistance, and expansion of therapeutic windows. In this review, we summarize recent advances in metal-based anticancer combinations from three mechanistic perspectives. First, we categorize combinations of metal-based agents with mechanistically distinct chemotherapeutics based on their ability to reinforce DNA damage, promote apoptotic execution, disrupt redox homeostasis, and exploit metabolic vulnerabilities. Second, we discuss the immunomodulatory functions of metallodrugs, emphasizing their capacity to induce immunogenic cell death and reprogram tumor microenvironment, thereby establishing a rational basis for combinations with immune checkpoint blockade. Third, we explore emerging multimodal strategies in which metal-based systems function as energy-responsive agents, enabling photodynamic, photothermal, or sonodynamic therapy and rational integration with other modalities. Collectively, these insights provide a robust mechanistic foundation to guide the rational design of next-generation metal-based combination therapies for improved cancer treatment.