Abstract
Therapeutic strategies targeting iron metabolism to disturb the physiological functions of tumor cells have emerged as promising avenues in cancer treatment. Deferoxamine (DFOM) is an effective FDA-approved iron chelator that actively eliminates iron from cells, inducing iron-related dysfunction. However, its use is considerably limited by off-target toxicities and the innate metabolic compensatory capacity of tumor cells. To address these challenges, herein, we developed a facile manganese-doped calcium phosphate mineralized nanoparticle loaded with DFOM (termed BSA@MnCaP@DFOM). These nanoparticles polarized tumor-associated macrophages to M1 phenotype via activating Toll-like receptor 4 (TLR4) pathway, thereby cutting off their iron supply to tumor cells. This promoted the iron depletion effect of DFOM, reduced ferritin heavy chain 1 (FTH1) expression, disrupted iron metabolism, and efficiently induced mitochondrial dysfunction in the highly iron-dependent 4 T1 breast cancer cells. Consequently, the treatment triggered immunogenic cell death in tumor cells, eliciting a robust antitumor T cells immune response. Combined with mitigation of the immunosuppressive microenvironment, tumor suppression was achieved (72.5 % inhibition rate). In summary, our nanoparticles offer a promising strategy for iron metabolism disruption-mediated breast cancer immunotherapy.