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Abstract

Immunotherapy, particularly immune checkpoint inhibition (ICI), has transformed cancer treatment and led to durable responses in subsets of patients. However, response rates remain low across many tumour types, and strategies to improve ICI efficacy are urgently needed. Metal-based chemotherapies, such as platinum (Pt)-containing agents like cisplatin and oxaliplatin, have long been used in oncology. Although oxaliplatin induces ICD, its systemic toxicity and inconsistent benefit in combination with ICI have limited its clinical applicability. Copper (Cu), unlike Pt, is a bioessential trace element required for mitochondrial respiration and redox regulation. These cellular processes are frequently upregulated in Cu-enriched tumour cells to support proliferation and metastasis. Historically, Cu chelation has been explored as a way to deprive tumour cells of this essential nutrient. More recently, an alternative strategy has emerged: delivering Cu therapeutically to induce a form of regulated cell death known as cuproptosis. This mechanism, and its potential to enhance anticancer immunity, remains underexplored in the context of immunotherapy. This thesis presents a systematic investigation of Cu in anticancer immunity, focusing on both therapeutic delivery and the influence of baseline Cu levels in the tumour microenvironment (TME). A liposomal formulation of the Cu complex of diethyldithiocarbamate (Cu(DDC)₂) was developed and shown to activate adaptive immune responses in syngeneic mouse tumour models. A comparative screen of Cu-binding compounds revealed that the ability to transport Cu intracellularly (ionophore-like activity) was associated with ICD induction. Although both Cu(DDC)₂ and a Cu complexation of clioquinol (Cu(CQ)₂) activated ICD markers, they elicited distinct transcriptional responses, suggesting compound-specific effects on cell death and immune activation. To assess the influence of baseline Cu content, CT26 and MC38 tumour models were characterized as high- and low-Cu environments with distinct isotopic signatures. Treatment with Cu(DDC)₂ or Cu(CQ)₂ in combination with ICI led to markedly different outcomes. CT26 showed enhanced therapeutic response, particularly during acute treatment, whereas MC38 displayed an antagonistic interaction. These findings support the therapeutic potential of Cu-based agents in cancer immunotherapy and highlight the importance of Cu carrier chemistry and tumour-specific Cu biology in guiding clinical development of Cu-based adjuncts to ICI.