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<p>Microsatellite-stable (MSS) colorectal cancer is largely refractory to PD-1 blockade due to its weak immunogenicity and an immune-excluded tumor microenvironment. Here, we developed an integrin α6-targeted photosensitizer, Ce6-RWYD, for tumor-selective photodynamic therapy (PDT). Ce6-RWYD exhibited minimal dark toxicity but induced strong light-activated cytotoxicity, accompanied by plasma membrane damage. Ce6-RWYD-mediated PDT also induced mitochondrial dysfunction and immunogenic cell death, while suppressing integrin α6-related downstream signaling. In vivo fluorescence imaging demonstrated enhanced tumor accumulation and prolonged retention of Ce6-RWYD compared with the talaporfin sodium (NPe6). In a CT26 subcutaneous tumor model, Ce6-RWYD-mediated PDT achieved robust antitumor efficacy, remodeled the tumor immune microenvironment, and showed favorable in vivo biosafety. Combination with anti-PD-1 further enhanced antitumor efficacy, accompanied by increased intratumoral CD8⁺ T-cell infiltration and reduced Gr-1⁺ myeloid cells. Collectively, these findings demonstrate that Ce6-RWYD-mediated PDT sensitizes MSS colorectal cancer to PD-1 blockade.</p> Graphical abstract <p></p>

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Integrin α6-targeted photodynamic therapy potentiates PD-1 blockade in MSS colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Ting Hu,
  • Qian-Kun Shi,
  • Qiao-Li Wang,
  • Ze-Rong Huang,
  • Wan-Qi Chen,
  • Lin-Na Luo,
  • Kai-Li Xie,
  • Fang Hu,
  • Jie Yang,
  • Jian-Jun Li,
  • Guo-Kai Feng

摘要

Microsatellite-stable (MSS) colorectal cancer is largely refractory to PD-1 blockade due to its weak immunogenicity and an immune-excluded tumor microenvironment. Here, we developed an integrin α6-targeted photosensitizer, Ce6-RWYD, for tumor-selective photodynamic therapy (PDT). Ce6-RWYD exhibited minimal dark toxicity but induced strong light-activated cytotoxicity, accompanied by plasma membrane damage. Ce6-RWYD-mediated PDT also induced mitochondrial dysfunction and immunogenic cell death, while suppressing integrin α6-related downstream signaling. In vivo fluorescence imaging demonstrated enhanced tumor accumulation and prolonged retention of Ce6-RWYD compared with the talaporfin sodium (NPe6). In a CT26 subcutaneous tumor model, Ce6-RWYD-mediated PDT achieved robust antitumor efficacy, remodeled the tumor immune microenvironment, and showed favorable in vivo biosafety. Combination with anti-PD-1 further enhanced antitumor efficacy, accompanied by increased intratumoral CD8⁺ T-cell infiltration and reduced Gr-1⁺ myeloid cells. Collectively, these findings demonstrate that Ce6-RWYD-mediated PDT sensitizes MSS colorectal cancer to PD-1 blockade.

Graphical abstract