A Necroptosis-Inducing Nickel(II) Complex for Immunotherapeutic Activation of Breast Cancer Stem Cells

Abstract

The immunotherapeutic anti-cancer stem cell (CSC) properties of a nickel(II) complex containing non-steroidal anti-inflammatory drug, diclofenac is reported. The nickel(II) complex 4 displays nanomolar potency towards breast CSCs, >264-fold greater than salinomycin (gold standard anti-breast CSC agent) and cisplatin (blockbuster anticancer metallodrug). In fact, 4 is more potent towards breast CSCs than any previously reported metal-containing compound. Notably, 4 exhibits significantly higher selectivity for breast CSCs over bulk breast cancer cells than salinomycin. Mechanistic studies suggest that 4 induces necroptosis and inhibits cyclooxygenase-2 expression (and thus perturbs the inhibitory damage-associated molecular pattern axis) in breast CSCs. Both factors contribute to an immunogenic phenotype in breast CSCs that does not exhibit all the hallmarks of immunogenic cell death. Further, breast CSCs dosed with 4 were efficiently phagocytosed by macrophages. Remarkably, when delivered as a polymeric nanoparticle formulation in a murine metastatic triple-negative breast cancer model, 4 significantly inhibits tumour growth and promotes immune system activation. The latter was characterised by T-cell and mature dendritic cell infiltration into the tumour and tumour-draining lymph nodes. To the best of our knowledge, 4 is among the first necroptosis-inducing metal complexes to evoke immunogenic-activating effects towards hard-to-kill breast cancer cells in vitro and in vivo.