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<p>Cancer immunotherapy holds promise for improving the efficacy of cancer treatment; however, low response rates remain a considerable challenge. Photodynamic therapy has a potential to be effective in immunotherapy, but it is limited by the inabilities to target tumor and limitation of reactive oxygen species (ROS) generation by hypoxia. Here, mitochondria-targeted zinc phthalocyanines (ZnPcs) are developed to precisely induce pyroptosis and activate immune responses. Cationic moieties incorporated in the ZnPc core allow strong localization in the mitochondrion and avoid aggregation of ZnPc, which serves as the highest site-specific production of ROS through the irradiation process. ZnPc-4 is among the synthesized derivatives that inhibit oxidative phosphorylation, relieving hypoxia and increasing type I/II ROS to cause mitochondrial dysfunction, which eventually triggers pyroptosis. Encapsulation of ZnPc-4 within DSPE-PEG2000-cRGDfk nanoparticle (ZnPc-NP) enhances its tumor-targeted capability and biocompatibility. <i>In vivo</i>, ZnPc-NP triggers immunogenic pyroptosis, eliciting potent anti-tumor immunity. In addition, ZnPc-NP combines with αPD-1, significantly inhibiting tumor metastasis and recurrence. This study establishes a dual-targeted photodynamic platform that overcomes microenvironmental constraints to potentiate cancer immunotherapy.</p>

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Dual-targeted phototherapeutic zinc phthalocyanine triggers pyroptosis for cancer immunotherapy

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • En-Li Yang,
  • Haozhe Dong,
  • Wu-Yin Wang,
  • Wen-Da Wang,
  • Nian Chen,
  • Weican Cui,
  • Su-Ran Li,
  • Wen-Tao Mo,
  • Qing Wang,
  • Yuan-Yuan Wang,
  • Qi-Chao Yang,
  • Hong Yi,
  • Aiwen Lei,
  • Zhi-Jun Sun

摘要

Cancer immunotherapy holds promise for improving the efficacy of cancer treatment; however, low response rates remain a considerable challenge. Photodynamic therapy has a potential to be effective in immunotherapy, but it is limited by the inabilities to target tumor and limitation of reactive oxygen species (ROS) generation by hypoxia. Here, mitochondria-targeted zinc phthalocyanines (ZnPcs) are developed to precisely induce pyroptosis and activate immune responses. Cationic moieties incorporated in the ZnPc core allow strong localization in the mitochondrion and avoid aggregation of ZnPc, which serves as the highest site-specific production of ROS through the irradiation process. ZnPc-4 is among the synthesized derivatives that inhibit oxidative phosphorylation, relieving hypoxia and increasing type I/II ROS to cause mitochondrial dysfunction, which eventually triggers pyroptosis. Encapsulation of ZnPc-4 within DSPE-PEG2000-cRGDfk nanoparticle (ZnPc-NP) enhances its tumor-targeted capability and biocompatibility. In vivo, ZnPc-NP triggers immunogenic pyroptosis, eliciting potent anti-tumor immunity. In addition, ZnPc-NP combines with αPD-1, significantly inhibiting tumor metastasis and recurrence. This study establishes a dual-targeted photodynamic platform that overcomes microenvironmental constraints to potentiate cancer immunotherapy.