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<p>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<sub>2</sub>@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<sub>2</sub> 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.</p> Graphical Abstract <p></p>

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Sonodynamic therapy-boosted biomimetic nanoplatform targets ferroptosis and CD47 as vulnerabilities for cancer immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月9日

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  • Haiqin Liao,
  • Mingyu Chen,
  • Zhipeng Liao,
  • Yi Luo,
  • Sijie Chen,
  • Wanlin Tan,
  • Long Wang,
  • Chengcheng Niu

摘要

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/MnO2@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 MnO2 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.

Graphical Abstract