Abstract

Immune checkpoint blockade (ICB) therapies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become established as part of standard care for pleural mesothelioma. However, few patients experience durable benefit, underscoring a need for strategies that enhance responsiveness to ICB. Given that intratumoural copper accumulation contributes to an immunosuppressive tumour microenvironment, we investigated whether copper homeostasis could be therapeutically targeted in mesothelioma. Copper homeostasis genes were upregulated in human mesothelioma and localised predominantly to malignant and stromal cells, whereas lymphocyte populations showed downregulation of these genes. In murine mesothelioma, copper-related genes were dynamically regulated during responses to ICB. Treatment with the clinically approved copper chelator Triethylenetetramine (TETA) reduced intratumoural copper, increased cytotoxic lymphocytes, and enriched inflammatory genes in tumour infiltrating myeloid and lymphoid compartments. Importantly, copper chelation improved anti-CTLA-4 and anti-PD-1 therapy in immunocompetent mesothelioma mouse models, leading to durable tumour control. These findings identify copper homeostasis as a promising target to enhance anti-tumour immunity in mesothelioma and support clinical evaluation of copper depletion in combination with first-line ICB.