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Objective <p>Cancer-associated fibroblasts (CAF) account for a high proportion in most solid tumors, including lung cancer, where they exert immunosuppressive function and thereby facilitate cancer progression. Photodynamic therapy (PDT) destroys malignant cells through photo-mediated ROS generation, but its effects on CAF have not been fully explored. The present study aims to investigate these effects and the involved molecular mechanism.</p> Materials and methods <p>The CAF model was established using L929 fibroblasts and Lewis lung cancer cells-derived conditioned medium (LLC CM). Laser-irradiated Chlorin e6 (Ce6) was harnessed to drive PDT. The biomarkers of CAF were detected by Western blotting. Intracellular oxidative stress was analyzed using fluorescence probes and flow cytometry. The dehydrogenase activity (cell viability) of CAF was assessed using the CCK-8 assay.</p> Results <p>High expression of α-SMA, FAP, and PDGFRβ was identified in the Lewis cell-derived conditioned medium-stimulated CAF. The photosensitizer Ce6 was effectively internalized by CAF without compromising cell dehydrogenase activity under the selected conditions. Further investigation revealed that the screened sublethal Ce6-PDT potentiated a more aggressive phenotype of CAF. Mechanistically, this effect was linked to the reactive oxygen species (ROS) generation and activation of the MAPK signaling pathway driven by oxidative stress. Suppression of oxidative stress and MAPK signaling successfully reversed the aforementioned effect of PDT on CAF activation.</p> Conclusion <p>Taken together, Ce6-mediated sublethal PDT under specific conditions further promotes CAF activation by oxidative stress and the downstream MAPK signaling pathway, thereby regulating the lung cancer microenvironment. As a study deciphering PDT-mediated regulation of CAF in the tumor immune microenvironment, our work constitutes a pioneering and highly significant exploratory effort.</p> Graphic abstract <p></p>

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Chlorin e6-mediated sublethal photodynamic therapy modulates biomarkers in a murine lung cancer–derived in vitro cancer-associated fibroblast model

  • 期刊论文

  • 发表日期：

    2026年7月2日

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  • Shuntianci Zhang,
  • Jun Shi,
  • Fan Leng,
  • Liu-Gen Li,
  • Chen-Yu Wang,
  • Ning Han,
  • Jun Hu,
  • Tong-Fei Li,
  • Xing-Chun Peng

摘要

Objective

Cancer-associated fibroblasts (CAF) account for a high proportion in most solid tumors, including lung cancer, where they exert immunosuppressive function and thereby facilitate cancer progression. Photodynamic therapy (PDT) destroys malignant cells through photo-mediated ROS generation, but its effects on CAF have not been fully explored. The present study aims to investigate these effects and the involved molecular mechanism.

Materials and methods

The CAF model was established using L929 fibroblasts and Lewis lung cancer cells-derived conditioned medium (LLC CM). Laser-irradiated Chlorin e6 (Ce6) was harnessed to drive PDT. The biomarkers of CAF were detected by Western blotting. Intracellular oxidative stress was analyzed using fluorescence probes and flow cytometry. The dehydrogenase activity (cell viability) of CAF was assessed using the CCK-8 assay.

Results

High expression of α-SMA, FAP, and PDGFRβ was identified in the Lewis cell-derived conditioned medium-stimulated CAF. The photosensitizer Ce6 was effectively internalized by CAF without compromising cell dehydrogenase activity under the selected conditions. Further investigation revealed that the screened sublethal Ce6-PDT potentiated a more aggressive phenotype of CAF. Mechanistically, this effect was linked to the reactive oxygen species (ROS) generation and activation of the MAPK signaling pathway driven by oxidative stress. Suppression of oxidative stress and MAPK signaling successfully reversed the aforementioned effect of PDT on CAF activation.

Conclusion

Taken together, Ce6-mediated sublethal PDT under specific conditions further promotes CAF activation by oxidative stress and the downstream MAPK signaling pathway, thereby regulating the lung cancer microenvironment. As a study deciphering PDT-mediated regulation of CAF in the tumor immune microenvironment, our work constitutes a pioneering and highly significant exploratory effort.

Graphic abstract