Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China.
Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China.
Front Immunol. 2024 Oct 17;15:1466180. doi: 10.3389/fimmu.2024.1466180. eCollection 2024.
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-FeO with C5aRA significantly improved the anti-tumor effect of PEG- FeO 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- FeO@C5aRA as a novel therapeutic strategy for breast cancer in clinical trials.
乳腺癌是全球女性中最常见的恶性肿瘤和癌症死亡的主要原因。铁死亡是一种最近发现的与肿瘤进展和治疗反应相关的铁依赖性调节细胞死亡。此外，越来越多的研究表明，铁死亡是一种有前途的消除癌细胞的方法，例如开发铁纳米颗粒作为治疗剂。然而，对铁死亡的抵抗是癌症的一个重要特征。因此，进一步研究铁死亡抵抗的机制以增强其肿瘤敏感性对于铁死亡靶向乳腺癌治疗至关重要。我们的结果表明，C5a/C5aR 途径的激活可以驱动对铁死亡的抵抗，并重塑乳腺癌免疫微环境。因此，用 C5aRA 加载 PEG-FeO 可以通过抑制铁死亡抵抗和增加巨噬细胞向 M1 表型极化来显著提高 PEG-FeO 的抗肿瘤作用。我们的研究结果提出了一种新的癌症治疗策略，将癌细胞金属代谢调节与免疫治疗相结合。该研究还为进一步评估 PEG-FeO@C5aRA 作为临床试验中治疗乳腺癌的一种新的治疗策略提供了支持。
