Navigating the Copper Chelation Highway: Tuning Copper for Coordination Chemistry for Tumor Control

The diverse chemical properties of copper (Cu) make it an attractive target in oncology. Cu plays central roles in angiogenesis, metastasis, redox regulation, and the activation of metalloenzymes that sustain tumor proliferation, making its homeostasis critical for cancer growth. Inspired by the clinical success of chelation therapy for heavy-metal poisoning and iron overload, metal-binding ligands are now either repurposed or newly designed and then structurally finetuned to modulate tumor copper levels. Diverse Cu-modulating strategies have emerged to disrupt Cu-dependent biochemical pathways and control tumor progression. These approaches can be grouped into two main categories: (1) Cu⁺and Cu²⁺chelators that directly induce copper-dependent cytotoxicity, and (2) Cu²⁺ionophores that facilitate intracellular copper transport and reductive release of Cu⁺ to selectively target specific protein partners. Rather than providing an exhaustive catalog, this work highlights how modern ligand design can manipulate Cu-protein interactions to inhibit tumor growth. Additionally, select compounds containing ^64/67Cu radioisotopes are assessed for their potential use in cancer diagnostics, therapy, and theragnostics by exploiting the radiometal's favorable decay characteristics and balancing crucial chelator requirements to suppress the metal's redox activity and ligand exchange lability amongst other desired properties and appending cell receptor recognizing structural motifs for optimal cell delivery. By combining structure-function and structure activity relationship studies with imaging-guided and combination therapies, this work collectively aims to examine the feasibility of Cu implementation in the next-generation therapeutics and diagnostics/theragnostics to precisely modulate tumor growth while improving clinical outcomes.