Liao Haiqin, Chen Mingyu, Liao Zhipeng, Luo Yi, Chen Sijie, Tan Wanlin, Wang Long, Niu Chengcheng
Department of Ultrasound, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
J Nanobiotechnology. 2025 Jun 9;23(1):432. doi: 10.1186/s12951-025-03485-w.
The efficacy of cancer immunotherapy is frequently hindered by the immunosuppressive "cold" tumor microenvironment. Inducing immunogenic cell death (ICD) may address this limitation. Ferroptosis, a form of ICD characterized by iron-dependent lipid peroxidation, has gained attention as a therapeutic target due to its inherent or therapy-induced susceptibility in refractory cancers and resistant tumor microenvironments. CD47, overexpressed on tumor cell membranes, enables immune evasion by suppressing macrophage-mediated surveillance, positioning it as a promising immune checkpoint target for macrophage-driven immunotherapy. Combining ferroptosis induction with CD47 blockade represents a strategic approach to enhance therapeutic outcomes. In this study, we developed a biomimetic nanoplatform-IR780/MnO@PLGA@cell membrane-PEP20 nanoparticles-featuring a shell derived from 4T1 cell membranes conjugated with the CD47-inhibitory peptide PEP20. This design enables tumor-targeted delivery while enhancing macrophage phagocytosis of tumor cells. The MnO core depletes intra-tumoral glutathione, downregulating glutathione peroxidase 4 and accumulating lipid peroxides to trigger ferroptosis. Concurrently, the ultrasound-responsive agent IR780 generates singlet oxygen under ultrasound irradiation, amplifying ferroptosis via oxidative stress. The resultant reactive oxygen species drive M2-to-M1 macrophage repolarization. Ferroptosis-mediated ICD further stimulates dendritic cell antigen presentation, activates cytotoxic T-cell immunity, and establishes durable immune memory. By exploiting tumor defense mechanisms as therapeutic vulnerabilities, this nanoplatform offers an innovative strategy for refractory cancer treatment.
癌症免疫疗法的疗效常常受到免疫抑制性“冷”肿瘤微环境的阻碍。诱导免疫原性细胞死亡（ICD）或许可以解决这一局限性。铁死亡是一种以铁依赖性脂质过氧化为特征的ICD形式，由于其在难治性癌症和耐药肿瘤微环境中的内在或治疗诱导的易感性，作为一种治疗靶点受到了关注。CD47在肿瘤细胞膜上过度表达，通过抑制巨噬细胞介导的监测实现免疫逃逸，使其成为巨噬细胞驱动的免疫疗法中一个有前景的免疫检查点靶点。将铁死亡诱导与CD47阻断相结合是提高治疗效果的一种策略性方法。在本研究中，我们开发了一种仿生纳米平台——IR780/MnO@PLGA@细胞膜-PEP20纳米颗粒，其外壳源自与CD47抑制肽PEP20偶联的4T1细胞膜。这种设计能够实现肿瘤靶向递送，同时增强巨噬细胞对肿瘤细胞的吞噬作用。MnO核心消耗肿瘤内的谷胱甘肽，下调谷胱甘肽过氧化物酶4并积累脂质过氧化物以触发铁死亡。同时，超声响应剂IR780在超声照射下产生单线态氧，通过氧化应激放大铁死亡。产生的活性氧驱动M2巨噬细胞向M1巨噬细胞重极化。铁死亡介导的ICD进一步刺激树突状细胞的抗原呈递，激活细胞毒性T细胞免疫，并建立持久的免疫记忆。通过利用肿瘤防御机制作为治疗弱点，这种纳米平台为难治性癌症治疗提供了一种创新策略。
