Antibody-based immunotherapies targeting disialoganglioside (GD2) have transformed the treatment landscape for high-risk neuroblastoma, yet nearly half of patients fail to achieve durable responses owing to resistant or refractory disease. This limited efficacy is largely attributed to the immunosuppressive tumour microenvironment (TME). Building on our prior work linking intratumoural copper accumulation to immune evasion, we reveal a previously unrecognised mechanism in which copper-driven neutrophil dysfunction suppresses antitumour immunity. We demonstrate that adjuvant copper chelation reprogrammes the neuroblastoma TME and enhances anti-GD2 antibody efficacy.
Using tetraethylenepentamine (TEPA) and its clinically approved analogue triethylenetetramine (TETA), we evaluated the therapeutic potential of copper chelation in immunocompetent neuroblastoma models. In the Th-MYCN model, TEPA reduced intratumoural copper and induced extensive immune remodelling as demonstrated using spatial and single-cell transcriptomics, multiplex immunohistochemistry, and cytokine profiling. Copper chelation restored antitumour immunity and promoted neutrophil egress and pro-inflammatory N1 polarisation within the TME, emphasising the emerging role of neutrophils as key mediators of antibody therapy. Mechanistically, we demonstrate that copper sequestration by neuroblastoma cells limits neutrophil effector functions in vitro, which can be restored by copper chelation to potentiate antibody-dependent cellular cytotoxicity.
To facilitate clinical translation, we evaluated TETA, an oral copper chelating agent currently approved for the treatment of Wilson’s disease, a disorder characterised by aberrant copper accumulation. In the syngeneic NXS2 model, combination therapy with TETA and anti-GD2 therapy achieved durable tumour control without relapse after treatment cessation. Efficacy was associated with infiltration of pro-inflammatory innate immune subsets, including N1 neutrophils, and treatment was well tolerated with no evidence of hepatic, renal, or systemic toxicity.
Collectively, these findings identify copper-driven neutrophil dysfunction as a mechanism of immune evasion in neuroblastoma and establish copper chelation as a non-toxic immunomodulatory strategy. Building on these results, this approach has advanced into the BEACON2 clinical trial, which is actively recruiting patients to evaluate copper chelation in combination with anti-GD2 immunotherapy.