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<p>Docetaxel (Doc), a widely used chemotherapeutic agent, was limited by suboptimal therapeutic efficacy and dose-limiting systemic toxicity due to the insufficiency of hydrophilicity and tumor-targeting specificity. To address this limitation, we developed an amphiphilic ferrocene-based polymer, PPEGMA-<i>b</i>-PFMMA (PF), to co-encapsulate Doc and the photosensitizer IR808, forming photothermally responsive nanoparticles (NPs) termed P8D NPs. P8D NPs significantly improved the aqueous stability and tumor-specific accumulation of both agents by leveraging a hydrogen peroxide (H₂O₂)-triggered drug release mechanism within the tumor microenvironment. Under near‑infrared (NIR) irradiation, P8D NPs generated substantial heat and a burst of reactive oxygen species (ROS), promoting NPs disintegration and drug release. Mechanistically, Doc induced nuclear to cytoplasmic translocation of HMGB1, while photothermal/photodynamic therapy (PTT/PDT) facilitated the extracellular release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens via ferroptosis and cell membrane rupture. Together, these actions enhanced dendritic cells (DCs) maturation, antigen presentation and cytotoxic CD8⁺ T cell infiltration in tumor, thereby effectively reversing the immunosuppressive tumor microenvironment. Remarkably, this combination strategy not only inhibited the growth of distant tumors but also established long-term anti-tumor immunological memory to prevent recurrence. This study demonstrates that ferrocene-based nanocarrier-mediated PTT/PDT synergizes with Doc to reactivate antitumor immunity through ferroptosis-induced immunogenic cell death (ICD).</p>

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Chemo-photothermal synergy ignites antitumor immunity via ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Jundong Lin,
  • Huikang Yang,
  • Zhihao Zou,
  • Lizhi Deng,
  • Xiaoxia Cai,
  • Muqi Chen,
  • Jiaquan Xu,
  • Wenjun Yin,
  • Biyan Wen,
  • Wenjie Xie,
  • Qianfeng Xu,
  • Guowei Zhong,
  • Zhenjie Wu,
  • Yanfei Chen,
  • Rihong Zhang,
  • Weicheng Tian,
  • Yixun Zhang,
  • Yusen Long,
  • Yize Li,
  • Zhaodong Han,
  • Yuxiang Liang,
  • Jianheng Ye,
  • Jianming Lu,
  • Yingke Liang,
  • Qishan Dai,
  • Fen Zou,
  • Huichan He,
  • Weide Zhong,
  • Yangjia Zhuo

摘要

Docetaxel (Doc), a widely used chemotherapeutic agent, was limited by suboptimal therapeutic efficacy and dose-limiting systemic toxicity due to the insufficiency of hydrophilicity and tumor-targeting specificity. To address this limitation, we developed an amphiphilic ferrocene-based polymer, PPEGMA-b-PFMMA (PF), to co-encapsulate Doc and the photosensitizer IR808, forming photothermally responsive nanoparticles (NPs) termed P8D NPs. P8D NPs significantly improved the aqueous stability and tumor-specific accumulation of both agents by leveraging a hydrogen peroxide (H₂O₂)-triggered drug release mechanism within the tumor microenvironment. Under near‑infrared (NIR) irradiation, P8D NPs generated substantial heat and a burst of reactive oxygen species (ROS), promoting NPs disintegration and drug release. Mechanistically, Doc induced nuclear to cytoplasmic translocation of HMGB1, while photothermal/photodynamic therapy (PTT/PDT) facilitated the extracellular release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens via ferroptosis and cell membrane rupture. Together, these actions enhanced dendritic cells (DCs) maturation, antigen presentation and cytotoxic CD8⁺ T cell infiltration in tumor, thereby effectively reversing the immunosuppressive tumor microenvironment. Remarkably, this combination strategy not only inhibited the growth of distant tumors but also established long-term anti-tumor immunological memory to prevent recurrence. This study demonstrates that ferrocene-based nanocarrier-mediated PTT/PDT synergizes with Doc to reactivate antitumor immunity through ferroptosis-induced immunogenic cell death (ICD).