AUTHOR=Yang Hong , Li Guiqing , Zhang Ji , Zhao Jing , Zhao Yunpei , Wu Yufei , Sun Zihan , Song Shuangshuang , Zou Ying , Zou Zhihao , Han Xiao , Deng Boshao , Wang Lulu , Rao Hang , Xu Guilian , Wang Shufeng , Guo Sheng , Ding Huanyu , Shi Yan , Wu Yuzhang , Chen Jian TITLE=A novel hollow iron nanoparticle system loading PEG-Fe3O4 with C5a receptor antagonist for breast cancer treatment JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1466180 DOI=10.3389/fimmu.2024.1466180 ISSN=1664-3224 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.