A novel hollow iron nanoparticle system loading PEG-Fe3O4 with C5a receptor antagonist for breast cancer treatment

Abstract

Breast cancer is the most diagnosed malignancy and major cause of cancer death among women population in the worldwide. Ferroptosis is a recently discovered iron-dependent regulated cell death involved in tumor progression and therapeutic response. Moreover, increasing studies have implied that ferroptosis is a promising approach to eliminating cancer cells like developing iron nanoparticles as a therapeutic agent. However, resistance to ferroptosis is a vital distinctive hallmark of cancer. Therefore, further investigation of the mechanism of ferroptosis resistance to enhance its tumor sensitivity is essential for ferroptosis-target breast cancer therapy. Our results revealed that the activation of C5a/C5aR pathway can drive resistance to ferroptosis and reshaping breast cancer immune microenvironment. Accordingly, loading PEG-Fe₃O₄ with C5aRA significantly improved the anti-tumor effect of PEG- Fe₃O₄ by inhibiting ferroptosis resistance and increasing macrophage polarization toward M1 phenotype. Our findings presented a novel cancer therapy strategy that combined cancer cell metal metabolism regulation and immunotherapy. The study also provided support for further evaluation of PEG- Fe₃O₄@C5aRA as a novel therapeutic strategy for breast cancer in clinical trials.

Keywords: C5a/C5aR pathway; PEG- Fe3O4@C5aRA; ferroptosis resistance; iron nanoparticles; macrophage polarization.